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{{Short description|Organelle in eukaryotic cells responsible for respiration}}
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{{Infobox microanatomy
| Name        = Mitochondrion
| Latin       = organella
| Image       = Animal mitochondrion diagram en.svg
| Caption     = Diagram of animal mitochondrion
| PartOf = [[Cell (biology)|Cell]]
| Pronunciation = {{IPAc-en|ˌ|m|aɪ|t|ə|ˈ|k|ɒ|n|d|r|i|ə|n}}<ref>{{Cite encyclopedia |url=http://www.lexico.com/definition/mitochondrion |archive-url=https://web.archive.org/web/20200102152331/https://www.lexico.com/definition/mitochondrion |archive-date=January 2, 2020 |title=mitochondrion |dictionary=[[Lexico]] UK English Dictionary |publisher=[[Oxford University Press]]}}</ref>
}}
{{Organelle diagram}}

A '''mitochondrion''' ({{plural form|'''mitochondria'''}}) is an [[organelle]] found in the [[cell (biology)|cells]] of most [[eukaryote]]s, such as [[animal]]s, [[plant]]s and [[fungi]]. Mitochondria have a double [[lipid bilayer|membrane]] structure and use [[aerobic respiration]] to generate [[adenosine triphosphate]] (ATP), which is used throughout the cell as a source of [[chemical energy]].<ref>{{cite book |vauthors=Campbell NA, Williamson B, Heyden RJ |title=Biology: Exploring Life |publisher=[[Pearson plc|Pearson]]/[[Prentice Hall]] |year=2006 |location=Boston, Massachusetts |url=http://www.phschool.com/el_marketing.html |isbn=978-0-13-250882-7 |access-date=January 6, 2009 |archive-date=November 2, 2014 |archive-url=https://web.archive.org/web/20141102041816/http://www.phschool.com/el_marketing.html |url-status=live }}</ref> They were discovered by [[Albert von Kölliker]] in 1857<ref name="Science in the News-2012">{{cite web | title=Mighty Mitochondria and Neurodegenerative Diseases | website=Science in the News | date=February 1, 2012 | url=https://sitn.hms.harvard.edu/flash/2012/issue111/ | access-date=April 24, 2022 | archive-date=April 6, 2022 | archive-url=https://web.archive.org/web/20220406093616/https://sitn.hms.harvard.edu/flash/2012/issue111/ | url-status=live }}</ref> in the voluntary muscles of insects. The term ''mitochondrion'', meaning a thread-like granule, was coined by [[Carl Benda]] in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase popularized by [[Philip Siekevitz]] in a 1957 ''[[Scientific American]]'' article of the same name.<ref name="Siekevitz-1957"/>

Some cells in some [[multicellular organism]]s lack mitochondria (for example, mature mammalian [[red blood cell]]s). The multicellular [[animal]] ''[[Henneguya zschokkei|Henneguya salminicola]]'' is known to have retained mitochondrion-related organelles despite a complete loss of their mitochondrial genome.<ref name="Karnkowska-2016" /><ref name="Le Page-2020">{{cite news |last1=Le Page |first1=Michael |title=Animal that doesn't need oxygen to survive discovered |url=https://www.newscientist.com/article/2235009-animal-that-doesnt-need-oxygen-to-survive-discovered/ |work=New Scientist |date=24 February 2020 }}</ref><ref name="Yahalomi-2020">{{cite journal | vauthors = Yahalomi D, Atkinson SD, Neuhof M, Chang ES, Philippe H, Cartwright P, Bartholomew JL, Huchon D | title = A cnidarian parasite of salmon (Myxozoa: ''Henneguya'') lacks a mitochondrial genome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 10 | pages = 5358–5363 | date = March 2020 | pmid = 32094163 | pmc = 7071853 | doi = 10.1073/pnas.1909907117 | bibcode = 2020PNAS..117.5358Y | doi-access = free }}</ref> A large number of [[unicellular organism]]s, such as [[microsporidia]], [[parabasalid]]s and [[diplomonad]]s, have reduced or transformed their mitochondria into other structures,<ref name="Henze-2003">{{cite journal | vauthors = Henze K, Martin W | title = Evolutionary biology: essence of mitochondria | journal = Nature | volume = 426 | issue = 6963 | pages = 127–128 | date = November 2003 | pmid = 14614484 | doi = 10.1038/426127a | doi-access = free | bibcode = 2003Natur.426..127H }}</ref> e.g. [[hydrogenosome]]s and [[mitosome]]s.<ref>{{cite journal | vauthors = Leger MM, Kolisko M, Kamikawa R, Stairs CW, Kume K, Čepička I, Silberman JD, Andersson JO, Xu F, Yabuki A, Eme L, Zhang Q, Takishita K, Inagaki Y, Simpson AG, Hashimoto T, Roger AJ | title = Organelles that illuminate the origins of ''Trichomonas'' hydrogenosomes and ''Giardia'' mitosomes | journal = Nature Ecology & Evolution | volume = 1 | issue = 4 | article-number = 0092 | date = April 2017 | pmid = 28474007 | pmc = 5411260 | doi = 10.1038/s41559-017-0092 | bibcode = 2017NatEE...1...92L }}</ref> The [[oxymonad]]s ''[[Monocercomonoides]]'', ''[[Streblomastix]]'', and ''Blattamonas'' completely lost their mitochondria.<ref name="Karnkowska-2016" /><ref name="Novák-2023" />

Mitochondria are commonly between 0.75 and 3&nbsp;[[micrometre|μm]]{{sup|2}} in cross section,<!-- the "area" seen through a microscope on the slide is actually a "cross section"--><ref name="Wiemerslage-2016">{{cite journal | vauthors = Wiemerslage L, Lee D | title = Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters | journal = Journal of Neuroscience Methods | volume = 262 | pages = 56–65 | date = March 2016 | pmid = 26777473 | pmc = 4775301 | doi = 10.1016/j.jneumeth.2016.01.008 }}</ref> but vary considerably in size and structure. Unless specifically [[Staining|stained]], they are not visible. The mitochondrion is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, [[intermembrane space]], [[inner mitochondrial membrane|inner membrane]], [[crista]]e, and [[mitochondrial matrix|matrix]].

In addition to supplying cellular energy, mitochondria are involved in other tasks, such as [[cell signaling|signaling]], [[cellular differentiation]], and [[apoptosis|cell death]], as well as maintaining control of the [[cell cycle]] and [[cell growth]].<ref name="McBride-2006" /> [[Mitochondrial biogenesis]] is in turn temporally coordinated with these cellular processes.<ref name="Valero-2014">{{cite journal | vauthors = Valero T | title = Mitochondrial biogenesis: pharmacological approaches | journal = Current Pharmaceutical Design | volume = 20 | issue = 35 | pages = 5507–5509 | year = 2014 | pmid = 24606795 | doi = 10.2174/138161282035140911142118 | hdl-access = free | quote = Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3].&nbsp;... Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. | hdl = 10454/13341 }}</ref><ref name="Sanchis-Gomar-2014">{{cite journal | vauthors = Sanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV | title = Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches | journal = Current Pharmaceutical Design | volume = 20 | issue = 35 | pages = 5619–5633 | year = 2014 | pmid = 24606801 | doi = 10.2174/1381612820666140306095106 | quote = Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria }}</ref>

Mitochondria are implicated in human disorders and conditions such as [[mitochondrial disease]]s,<ref>{{cite journal |vauthors=Gardner A, Boles RG |title=Is a 'Mitochondrial Psychiatry' in the Future? A Review |journal=Curr. Psychiatry Rev. |volume=1 |issue=3 |pages=255–271 |year=2005 |doi=10.2174/157340005774575064}}</ref> [[Heart failure|cardiac dysfunction]],<ref>{{cite journal | vauthors = Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL | title = Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure | journal = Journal of Molecular and Cellular Cardiology | volume = 33 | issue = 6 | pages = 1065–1089 | date = June 2001 | pmid = 11444914 | doi = 10.1006/jmcc.2001.1378 }}</ref> heart failure,<ref name="Dorn-2015">{{cite journal | vauthors = Dorn GW, Vega RB, Kelly DP | title = Mitochondrial biogenesis and dynamics in the developing and diseased heart | journal = Genes & Development | volume = 29 | issue = 19 | pages = 1981–1991 | date = October 2015 | pmid = 26443844 | pmc = 4604339 | doi = 10.1101/gad.269894.115 }}</ref> and [[autism]].<ref name="Griffiths-2017">{{cite journal |vauthors=Griffiths KK, Levy RJ |title=Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms |journal=Oxidative Medicine and Cellular Longevity |volume=2017 |article-number=4314025 |date=2017 |pmid=28630658 |pmc=5467355 |doi=10.1155/2017/4314025 |doi-access=free}}</ref>

The number of mitochondria in a cell vary widely by [[organism]], [[Tissue (biology)|tissue]], and cell type. A mature red blood cell has no mitochondria,<ref name="Ney-2011">{{cite journal | vauthors = Ney PA | title = Normal and disordered reticulocyte maturation | journal = Current Opinion in Hematology | volume = 18 | issue = 3 | pages = 152–157 | date = May 2011 | pmid = 21423015 | pmc = 3157046 | doi = 10.1097/MOH.0b013e328345213e }}</ref> whereas a [[hepatocyte|liver cell]] can have more than 2000.<ref name="Alberts-2005">{{cite book | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P |year=2005 |title=Molecular Biology of the Cell |publisher=Garland Publishing Inc. |location=New York |isbn=978-0-8153-4105-5}}</ref><ref name="Voet-2006">{{cite book | vauthors = Voet D, Voet JC, Pratt CW |title=Fundamentals of Biochemistry |edition=2nd |publisher=John Wiley and Sons, Inc. |year=2006 |pages=[https://archive.org/details/fundamentalsofbi00voet_0/page/547 547, 556] |isbn=978-0-471-21495-3 |url=https://archive.org/details/fundamentalsofbi00voet_0/page/547 }}</ref>

Although most of a [[eukaryotic cell]]'s [[DNA]] is contained in the [[cell nucleus]], the mitochondrion has [[mitochondrial DNA|its own genome]] ("mitogenome") that is similar to [[bacteria]]l genomes.<ref>{{cite journal | vauthors = Andersson SG, Karlberg O, Canbäck B, Kurland CG | title = On the origin of mitochondria: a genomics perspective | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 358 | issue = 1429 | pages = 165–77; discussion 177–9 | date = January 2003 | pmid = 12594925 | pmc = 1693097 | doi = 10.1098/rstb.2002.1193 | author4-link = Charles Kurland | author1-link = Siv G. E. Andersson }}</ref> This finding has led to general acceptance of [[symbiogenesis]] (endosymbiotic theory) – that free-living prokaryotic ancestors of modern mitochondria permanently fused with eukaryotic cells in the distant past, evolving such that modern animals, plants, fungi, and other eukaryotes [[Cellular respiration|respire]] to generate [[Adenosine triphosphate|cellular energy]].<ref name="Gabaldón-2021">{{cite journal | vauthors = Gabaldón T | title = Origin and Early Evolution of the Eukaryotic Cell | journal = Annual Review of Microbiology | volume = 75 | issue = 1 | pages = 631–647 | date = October 2021 | pmid = 34343017 | doi = 10.1146/annurev-micro-090817-062213 }}</ref>

== Structure ==
Mitochondria may have a number of different shapes.<ref name="British Society for Cell Biology">{{cite web|title=Mitochondrion – much more than an energy converter|url=http://www.bscb.org/?url=softcell/mito|publisher=British Society for Cell Biology|access-date=August 19, 2013|archive-date=April 4, 2019|archive-url=https://web.archive.org/web/20190404173821/https://bscb.org/?url=softcell%2Fmito|url-status=live}}</ref> A mitochondrion contains outer and inner membranes composed of [[phospholipid bilayer]]s and [[protein]]s.<ref name="Alberts-2005" /> The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion:
# The outer mitochondrial membrane,
# The intermembrane space (the space between the outer and inner membranes),
# The inner mitochondrial membrane,
# The [[crista]]e space (formed by infoldings of the inner membrane), and
# The [[mitochondrial matrix|matrix]] (space within the inner membrane), which is a fluid.
Mitochondria have folding to increase surface area, which in turn increases ATP (adenosine triphosphate) production.
Mitochondria stripped of their outer membrane are called [[mitoplast]]s.

===Outer membrane===
The '''outer mitochondrial membrane''', which encloses the entire organelle, is 60 to 75 [[angstrom]]s (Å) thick. It has a protein-to-phospholipid ratio similar to that of the [[cell membrane]] (about 1:1 by weight). It contains large numbers of [[integral membrane protein]]s called [[porin (protein)|porins]]. A major trafficking protein is the pore-forming [[voltage-dependent anion channel]] (VDAC). The [[Voltage-dependent anion channel#Biological function|VDAC]] is the primary transporter of [[nucleotide]]s, [[ion]]s and [[metabolite]]s between the [[cytosol]] and the intermembrane space.<ref name="Blachly-Dyson-2001">{{cite journal | vauthors = Blachly-Dyson E, Forte M | title = VDAC channels | journal = IUBMB Life | volume = 52 | issue = 3–5 | pages = 113–118 | date = September 2001 | pmid = 11798022 | doi = 10.1080/15216540152845902 | doi-access = free }}</ref><ref name="Hoogenboom-2007">{{cite journal | vauthors = Hoogenboom BW, Suda K, Engel A, Fotiadis D | title = The supramolecular assemblies of voltage-dependent anion channels in the native membrane | journal = Journal of Molecular Biology | volume = 370 | issue = 2 | pages = 246–255 | date = July 2007 | pmid = 17524423 | doi = 10.1016/j.jmb.2007.04.073 }}</ref> It is formed as a [[beta barrel]] that spans the outer membrane, similar to that in the [[gram-negative]] [[bacterial outer membrane]].<ref name="Zeth-2010">{{cite journal | vauthors = Zeth K | title = Structure and evolution of mitochondrial outer membrane proteins of beta-barrel topology | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1797 | issue = 6–7 | pages = 1292–1299 | date = June 2010 | pmid = 20450883 | doi = 10.1016/j.bbabio.2010.04.019 | doi-access = free }}</ref> Larger proteins can enter the mitochondrion if a signaling sequence at their [[N-terminus]] binds to a large multisubunit [[Mitochondrial membrane transport protein|protein]] called [[Translocase of the outer membrane|translocase in the outer membrane]], which then [[active transport|actively moves]] them across the membrane.<ref name="Herrmann-2000">{{cite journal | vauthors = Herrmann JM, Neupert W | title = Protein transport into mitochondria | journal = Current Opinion in Microbiology | volume = 3 | issue = 2 | pages = 210–214 | date = April 2000 | pmid = 10744987 | doi = 10.1016/S1369-5274(00)00077-1 | url = http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-7488-5 }}</ref> Mitochondrial [[protein precursor|pro-proteins]] are imported through specialised translocation complexes.

The outer membrane also contains [[enzyme]]s involved in such diverse activities as the elongation of [[fatty acid]]s, [[oxidation]] of [[epinephrine]], and the [[Biodegradation|degradation]] of [[tryptophan]]. These enzymes include [[monoamine oxidase]], [[rotenone]]-insensitive NADH-cytochrome c-reductase, [[kynurenine]] [[hydroxylase]] and fatty acid Co-A [[ligase]]. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to cell death.<ref name="Chipuk-2006">{{cite journal | vauthors = Chipuk JE, Bouchier-Hayes L, Green DR | title = Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario | journal = Cell Death and Differentiation | volume = 13 | issue = 8 | pages = 1396–1402 | date = August 2006 | pmid = 16710362 | doi = 10.1038/sj.cdd.4401963 | doi-access = free }}</ref> The outer mitochondrial membrane can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria.<ref name="Hayashi-2009"/> Outside the outer membrane are small (diameter: 60 Å) particles named sub-units of Parson.

===Intermembrane space===
The '''mitochondrial intermembrane space''' is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the [[cytosol]].<ref name="Alberts-2005"/> However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the [[cytosol]]. One [[protein]] that is localized to the intermembrane space in this way is [[cytochrome c]].<ref name="Chipuk-2006"/>

===Inner membrane===
{{Main|Inner mitochondrial membrane}}

The inner mitochondrial membrane contains proteins with three types of functions:<ref name="Alberts-2005"/>
# Those that perform the [[electron transport chain]] [[redox]] reactions
# [[ATP synthase]], which generates [[Adenosine triphosphate|ATP]] in the matrix
# Specific [[membrane transport protein|transport proteins]] that regulate [[metabolite]] passage into and out of the [[mitochondrial matrix]]

It contains more than 151 different [[polypeptide]]s, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1&nbsp;protein for 15&nbsp;phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.<ref name="Schenkel-2014">{{cite journal | vauthors = Schenkel LC, Bakovic M | title = Formation and regulation of mitochondrial membranes | journal = International Journal of Cell Biology | volume = 2014 | article-number = 709828 | date = January 2014 | pmid = 24578708 | pmc = 3918842 | doi = 10.1155/2014/709828 | doi-access = free }}</ref> Additionally, the inner membrane is rich in an unusual phospholipid, [[cardiolipin]]. This phospholipid was originally discovered in [[Bos taurus|cow]] hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.<ref name="McMillin-2002">{{cite journal | vauthors = McMillin JB, Dowhan W | title = Cardiolipin and apoptosis | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1585 | issue = 2–3 | pages = 97–107 | date = December 2002 | pmid = 12531542 | doi = 10.1016/S1388-1981(02)00329-3 }}</ref> Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable,<ref name="Alberts-2005"/> and its disruption can lead to multiple clinical disorders including neurological disorders and cancer.<ref>{{cite journal | vauthors = Bautista JS, Falabella M, Flannery PJ, Hanna MG, Heales SJ, Pope SA, Pitceathly RD | title = Advances in methods to analyse cardiolipin and their clinical applications | journal = Trends in Analytical Chemistry | volume = 157 | article-number = 116808 | date = December 2022 | pmid = 36751553 | pmc = 7614147 | doi = 10.1016/j.trac.2022.116808 }}</ref> Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the [[translocase of the inner membrane]] (TIM) complex or via [[OXA1L]].<ref name="Herrmann-2000"/> In addition, there is a membrane potential across the inner membrane, formed by the action of the [[enzyme]]s of the [[electron transport chain]]. Inner membrane [[mitochondrial fusion|fusion]] is mediated by the inner membrane protein [[OPA1]].<ref name="Youle-2012">{{cite journal | vauthors = Youle RJ, van der Bliek AM | title = Mitochondrial fission, fusion, and stress | journal = Science | volume = 337 | issue = 6098 | pages = 1062–1065 | date = August 2012 | pmid = 22936770 | pmc = 4762028 | doi = 10.1126/science.1219855 | bibcode = 2012Sci...337.1062Y }}</ref>

====Cristae====
[[File:MitochondrionCAM.jpg|thumb|250 px|right|Cross-sectional image of cristae in a [[rat]] liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane]]
{{Main|Crista}}

The inner mitochondrial membrane is compartmentalized into numerous folds called [[crista]]e, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. For typical liver mitochondria, the area of the inner membrane is about five times as large as that of the outer membrane. This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae. Mitochondria within the same cell can have substantially different crista-density, with the ones that are required to produce more energy having much more crista-membrane surface.<ref name="Cserép-2018">{{cite journal | vauthors = Cserép C, Pósfai B, Schwarcz AD, Dénes Á | title = Mitochondrial Ultrastructure Is Coupled to Synaptic Performance at Axonal Release Sites | journal = eNeuro | volume = 5 | issue = 1 | pages = ENEURO.0390–17.2018 | date = 2018 | pmid = 29383328 | pmc = 5788698 | doi = 10.1523/ENEURO.0390-17.2018 }}</ref> These folds are studded with small round bodies known as [[F-ATPase|F{{sub|1}} particles]] or oxysomes.<ref name="Mannella-2006">{{cite journal | vauthors = Mannella CA | title = Structure and dynamics of the mitochondrial inner membrane cristae | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1763 | issue = 5–6 | pages = 542–548 | year = 2006 | pmid = 16730811 | doi = 10.1016/j.bbamcr.2006.04.006 | doi-access =}}</ref>

===Matrix===
{{Main|Mitochondrial matrix}}
The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total proteins in a mitochondrion.<ref name="Alberts-2005"/> The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial [[ribosomes]], [[tRNA]], and several copies of the [[mitochondrial DNA]] [[genome]]. Of the enzymes, the major functions include oxidation of [[pyruvate]] and [[fatty acids]], and the [[citric acid cycle]].<ref name="Alberts-2005" /> The DNA molecules are packaged into nucleoids by proteins, one of which is [[TFAM]].<ref>{{cite journal | vauthors = Bogenhagen DF | title = Mitochondrial DNA nucleoid structure | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1819 | issue = 9–10 | pages = 914–920 | date = September 2012 | pmid = 22142616 | doi = 10.1016/j.bbagrm.2011.11.005 }}</ref>

== Function ==
The most prominent roles of mitochondria are to produce the energy currency of the cell, [[Adenosine triphosphate|ATP]] (i.e., phosphorylation of [[Adenosine diphosphate|ADP]]), through respiration and to regulate cellular [[metabolism]].<ref name="Voet-2006"/> The central set of reactions involved in ATP production are collectively known as the [[citric acid cycle]], or the [[Hans Adolf Krebs|Krebs]] cycle, and [[oxidative phosphorylation]]. However, the mitochondrion has many other functions in addition to the production of ATP.

===Energy conversion===
A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of [[glucose]]: [[pyruvate]], and [[NADH]], which are produced in the cytosol.<ref name="Voet-2006"/> This type of [[cellular respiration]], known as [[aerobic respiration]], is dependent on the presence of [[oxygen]]. When oxygen is limited, the glycolytic products will be metabolized by [[Fermentation (biochemistry)|anaerobic fermentation]], a process that is independent of the mitochondria.<ref name="Voet-2006"/> The production of ATP from glucose and oxygen has an approximately 13-times higher yield during aerobic respiration compared to fermentation.<ref>{{cite journal | vauthors = Rich PR | title = The molecular machinery of Keilin's respiratory chain | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 6 | pages = 1095–1105 | date = December 2003 | pmid = 14641005 | doi = 10.1042/BST0311095 }}</ref> Plant mitochondria can also produce a limited amount of ATP either by breaking the sugar produced during photosynthesis or without oxygen by using the alternate substrate [[nitrite]].<ref name="Stoimenova-2007">{{cite journal | vauthors = Stoimenova M, Igamberdiev AU, Gupta KJ, Hill RD | title = Nitrite-driven anaerobic ATP synthesis in barley and rice root mitochondria | journal = Planta | volume = 226 | issue = 2 | pages = 465–474 | date = July 2007 | pmid = 17333252 | doi = 10.1007/s00425-007-0496-0 | bibcode = 2007Plant.226..465S }}</ref> ATP crosses out through the inner membrane with the help of a [[ATP–ADP translocase|specific protein]], and across the outer membrane via [[Porin (protein)|porins]].<ref name="Neupert-1997">{{cite journal | vauthors = Neupert W | title = Protein import into mitochondria | journal = Annual Review of Biochemistry | volume = 66 | pages = 863–917 | year = 1997 | pmid = 9242927 | doi = 10.1146/annurev.biochem.66.1.863 }}</ref> After conversion of ATP to [[Adenosine diphosphate|ADP]] by [[dephosphorylation]] that releases energy, ADP returns via the same route.

====Pyruvate and the citric acid cycle====
{{Main|Citric acid cycle}}

[[Pyruvate]] molecules produced by [[glycolysis]] are [[active transport|actively transported]] across the inner mitochondrial membrane, and into the matrix where they can either be [[Redox|oxidized]] and combined with [[coenzyme A]] to form CO{{sub|2}}, [[acetyl-CoA]], and [[NADH]],<ref name="Voet-2006" /> or they can be [[carboxylated]] (by [[pyruvate carboxylase]]) to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle and is therefore an [[anaplerotic reaction]], increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g., in [[striated muscle tissue|muscle]]) are suddenly increased by activity.<ref name="Stryer-1995">{{cite book | vauthors = Stryer L | title=In: Biochemistry. |chapter= Citric acid cycle. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773 |isbn= 0-7167-2009-4 }}</ref>

In the citric acid cycle, all the intermediates (e.g. [[citrate]], [[Isocitric acid|iso-citrate]], [[Alpha-Ketoglutaric acid|alpha-ketoglutarate]], succinate, [[Fumaric acid|fumarate]], [[Malic acid|malate]] and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an [[Anaplerotic reactions|anaplerotic]] effect, and its removal has a cataplerotic effect. These anaplerotic and [[cataplerotic]] reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of [[Adenosine triphosphate|ATP]] production by the mitochondrion, and thus the availability of ATP to the cell.<ref name="Stryer-1995" />

Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the [[beta-oxidation]] of [[fatty acids]], is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO{{sub|2}} and water, with the energy thus released captured in the form of ATP.<ref name="Stryer-1995" />

In the liver, the [[carboxylation]] of [[cytosol]]ic pyruvate into intra-mitochondrial oxaloacetate is an early step in the [[gluconeogenesis|gluconeogenic]] pathway, which converts [[lactic acid|lactate]] and de-aminated [[alanine]] into glucose,<ref name="Voet-2006" /><ref name="Stryer-1995" /> under the influence of high levels of [[glucagon]] and/or [[epinephrine]] in the blood.<ref name="Stryer-1995" /> Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted to cytosolic oxaloacetate, and ultimately to glucose, in a process that is almost the reverse of [[glycolysis]].<ref name="Stryer-1995" />

The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of [[succinate dehydrogenase]], which is bound to the inner mitochondrial membrane as part of Complex II.<ref>{{cite journal | vauthors = King A, Selak MA, Gottlieb E | title = Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer | journal = Oncogene | volume = 25 | issue = 34 | pages = 4675–4682 | date = August 2006 | pmid = 16892081 | doi = 10.1038/sj.onc.1209594 | doi-access =}}</ref> The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of [[NADH]] and one molecule of [[FADH2|FADH{{sub|2}}]]) that are a source of electrons for the [[electron transport chain]], and a molecule of [[Guanosine triphosphate|GTP]] (which is readily converted to an ATP).<ref name="Voet-2006"/>

==== O{{sub|2}} and NADH: energy-releasing reactions ====
{{Main|Oxidative phosphorylation|electron transport chain}}
[[File:Electron transport chain.svg|thumb|400px|Electron transport chain in the mitochondrial intermembrane space]]

The electrons from NADH and FADH{{sub|2}} are transferred to oxygen (O{{sub|2}}) and hydrogen (protons) in several steps via an electron transport chain. NADH and FADH{{sub|2}} molecules are produced within the matrix via the citric acid cycle and in the cytoplasm by [[glycolysis]]. [[Reducing equivalent]]s from the cytoplasm can be imported via the [[malate-aspartate shuttle]] system of [[antiporter]] proteins or fed into the electron transport chain using a [[glycerol phosphate shuttle]].<ref name="Voet-2006"/>

The major energy-releasing reactions<ref name="Voet-2004">{{cite book | vauthors = Voet D, Voet JG |title=Biochemistry |date=2004 |publisher=Wiley |location=New York, NY |isbn=978-0-471-19350-0 |edition=3rd | page = 804 }}</ref><ref name="Atkins-2006">{{cite book | vauthors = Atkins P, de Paula J | date = 2006 | chapter = Impact on biochemistry: Energy conversion in biological cells | title = Physical Chemistry | edition = 8th | pages = 225–229 | publisher = Freeman | location = New York | isbn = 978-0-7167-8759-4 }}</ref> that make the mitochondrion the "powerhouse of the cell" occur at [[Electron transport chain#Mitochondrial redox carriers|protein complexes I, III and IV]] in the inner mitochondrial membrane ([[NADH dehydrogenase (ubiquinone)]], [[Coenzyme Q - cytochrome c reductase|cytochrome c reductase]], and [[cytochrome c oxidase]]). At [[complex IV]], O<sub>2</sub> reacts with the reduced form of iron in [[cytochrome c]]:

:{{chem2 | O2 + 4 H+(aq) + 4 Fe(2+)(cyt c) -> 2 H2O + 4 Fe(3+)(cyt c) }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -218 kJ/mol

releasing a lot of [[Gibbs free energy|free energy]]<ref name="Atkins-2006"/><ref name="Voet-2004"/> from the reactants without breaking bonds of an organic fuel. The free energy put in to remove an electron from Fe<sup>2+</sup> is released at [[complex III]] when Fe<sup>3+</sup> of cytochrome c reacts to oxidize [[ubiquinol]] (QH<sub>2</sub>):

:{{chem2 | 2 Fe(3+)(cyt c) + QH2 -> 2 Fe(2+)(cyt c) + Q + 2 H+(aq) }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -30 kJ/mol

The [[ubiquinone]] (Q) generated reacts, in [[complex I]], with NADH:

:{{chem2 |Q + H+(aq) + NADH -> QH2 + NAD+ }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -81 kJ/mol

While the reactions are controlled by an electron transport chain, free electrons are not amongst the reactants or products in the three reactions shown and therefore do not affect the free energy released, which is used to pump [[Hydrogen ion|protons]] (H{{sup|+}}) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming [[reactive oxygen species]] such as [[superoxide]].<ref name="Voet-2006" /> This can cause [[oxidative stress]] in the mitochondria and may contribute to the decline in mitochondrial function associated with aging.<ref name="Huang-2004">{{cite journal | vauthors = Huang H, Manton KG | title = The role of oxidative damage in mitochondria during aging: a review | journal = Frontiers in Bioscience | volume = 9 | issue = 1–3 | pages = 1100–1117 | date = May 2004 | pmid = 14977532 | doi = 10.2741/1298 }}</ref>

As the proton concentration increases in the intermembrane space, a strong [[electrochemical gradient]] is established across the inner membrane. The protons can return to the matrix through the [[ATP synthase]] complex, and their potential energy is used to synthesize [[Adenosine triphosphate|ATP]] from ADP and inorganic phosphate (P{{sub|i}}).<ref name="Voet-2006"/> This process is called [[chemiosmosis]], and was first described by [[Peter D. Mitchell|Peter Mitchell]],<ref name="Mitchell-1967a">{{cite journal | vauthors = Mitchell P, Moyle J | title = Chemiosmotic hypothesis of oxidative phosphorylation | journal = Nature | volume = 213 | issue = 5072 | pages = 137–139 | date = January 1967 | pmid = 4291593 | doi = 10.1038/213137a0 | bibcode = 1967Natur.213..137M }}</ref><ref name="Mitchell-1967b">{{cite journal | vauthors = Mitchell P | title = Proton current flow in mitochondrial systems | journal = Nature | volume = 214 | issue = 5095 | pages = 1327–1328 | date = June 1967 | pmid = 6056845 | doi = 10.1038/2141327a0 | bibcode = 1967Natur.214.1327M }}</ref> who was awarded the 1978 [[Nobel Prize in Chemistry]] for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to [[Paul D. Boyer]] and [[John E. Walker]] for their clarification of the working mechanism of ATP synthase.<ref>{{cite web |last =Nobel Foundation |title =Chemistry 1997 |url =http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |access-date =December 16, 2007 |archive-date =July 8, 2007 |archive-url =https://web.archive.org/web/20070708165350/http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |url-status =live }}</ref>

====Heat production====
Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as ''proton leak'' or [[mitochondrial uncoupling]] and is due to the [[facilitated diffusion]] of protons into the matrix. The process results in the unharnessed potential energy of the proton [[Electrochemistry|electrochemical]] gradient being released as heat.<ref name="Voet-2006"/> The process is mediated by a proton channel called [[thermogenin]], or [[UCP1]].<ref name="Mozo-2005">{{cite journal | vauthors = Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F | title = Thermoregulation: what role for UCPs in mammals and birds? | journal = Bioscience Reports | volume = 25 | issue = 3–4 | pages = 227–249 | date = November 2005 | pmid = 16283555 | doi = 10.1007/s10540-005-2887-4 }}</ref> Thermogenin is primarily found in [[brown adipose tissue]], or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.<ref name="Mozo-2005"/>

=== Mitochondrial fatty acid synthesis ===
{{Main|Mitochondrial fatty acid synthesis}}

Mitochondrial fatty acid synthesis (mtFAS) is essential for cellular respiration and mitochondrial biogenesis.<ref>{{cite journal | vauthors = Kastaniotis AJ, Autio KJ, Kerätär JM, Monteuuis G, Mäkelä AM, Nair RR, Pietikäinen LP, Shvetsova A, Chen Z, Hiltunen JK | title = Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1862 | issue = 1 | pages = 39–48 | date = January 2017 | pmid = 27553474 | doi = 10.1016/j.bbalip.2016.08.011 }}</ref> In response to mitochondrial acetyl-CoA availability, mtFAS builds acyl chains on the [[4'-phosphopantetheine]] group of the matrix-soluble scaffold protein [[Acyl carrier protein|ACP]] (holo-ACP), producing [[acyl-ACP]] species with varying chain lengths of at least eight carbons.<ref>{{Cite journal |last1=Wedan |first1=Riley J. |last2=Longenecker |first2=Jacob Z. |last3=Nowinski |first3=Sara M. |date=January 2024 |title=Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism |journal=Cell Metabolism |language=en |volume=36 |issue=1 |pages=36–47 |doi=10.1016/j.cmet.2023.11.017 |pmc=10843818 |pmid=38128528 |doi-access=free}}</ref>

Among these, [[octanoyl-ACP]] (C8) serves as the precursor for [[lipoic acid]] biosynthesis.<ref name="Nowinski-2018">{{cite journal | vauthors = Nowinski SM, Van Vranken JG, Dove KK, Rutter J | title = Impact of Mitochondrial Fatty Acid Synthesis on Mitochondrial Biogenesis | journal = Current Biology | volume = 28 | issue = 20 | pages = R1212–R1219 | date = October 2018 | pmid = 30352195 | pmc = 6258005 | doi = 10.1016/j.cub.2018.08.022 | bibcode = 2018CBio...28R1212N }}</ref> Since lipoic acid is a cofactor for key mitochondrial enzyme complexes, including the [[pyruvate dehydrogenase complex]] (PDC), [[Oxoglutarate dehydrogenase complex|α-ketoglutarate dehydrogenase complex]] (OGDC), [[2-oxoadipate dehydrogenase complex]] (OADHC), [[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain α-ketoacid dehydrogenase complex]] (BCKDC), and the [[glycine cleavage system]] (GCS), mtFAS significantly influences energy metabolism.<ref>{{cite journal | vauthors = Wehbe Z, Behringer S, Alatibi K, Watkins D, Rosenblatt D, Spiekerkoetter U, Tucci S | title = The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1864 | issue = 11 | pages = 1629–1643 | date = November 2019 | pmid = 31376476 | doi = 10.1016/j.bbalip.2019.07.012 }}</ref>

In contrast, longer-chain acyl-ACPs (C12–C18) [[Allosteric regulation|allosterically]] activate the network of [[LYRM protein]]s, which comprises at least 12 members in humans and regulates mitochondrial [[Translation (biology)|translation]], [[Iron–sulfur cluster|iron-sulfur cluster]] biogenesis, and the assembly of electron transport chain complexes.<ref name="Van Vranken-2018">{{Cite journal |last1=Van Vranken |first1=Jonathan G. |last2=Nowinski |first2=Sara M. |last3=Clowers |first3=Katie J. |last4=Jeong |first4=Mi-Young |last5=Ouyang |first5=Yeyun |last6=Berg |first6=Jordan A. |last7=Gygi |first7=Jeremy P. |last8=Gygi |first8=Steven P. |last9=Winge |first9=Dennis R. |last10=Rutter |first10=Jared |date=August 2018 |title=ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly |journal=Molecular Cell |language=en |volume=71 |issue=4 |pages=567–580.e4 |doi=10.1016/j.molcel.2018.06.039 |pmc=6104058 |pmid=30118679 |doi-access=free}}</ref><ref name="Masud-2019">{{Cite journal |last1=Masud |first1=Ali J. |last2=Kastaniotis |first2=Alexander J. |last3=Rahman |first3=M. Tanvir |last4=Autio |first4=Kaija J. |last5=Hiltunen |first5=J. Kalervo |date=December 2019 |title=Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |language=en |volume=1866 |issue=12 |article-number=118540 |doi=10.1016/j.bbamcr.2019.118540 |issn=0167-4889 |doi-access=free}}</ref> MtFAS and ACP thus coordinate the activation of mitochondrial respiration in response to substrate availability.<ref name="Van Vranken-2018" /><ref name="Nowinski-2020">{{Cite journal |last1=Nowinski |first1=Sara M |last2=Solmonson |first2=Ashley |last3=Rusin |first3=Scott F |last4=Maschek |first4=J Alan |last5=Bensard |first5=Claire L |last6=Fogarty |first6=Sarah |last7=Jeong |first7=Mi-Young |last8=Lettlova |first8=Sandra |last9=Berg |first9=Jordan A |last10=Morgan |first10=Jeffrey T |last11=Ouyang |first11=Yeyun |last12=Naylor |first12=Bradley C |last13=Paulo |first13=Joao A |last14=Funai |first14=Katsuhiko |last15=Cox |first15=James E |date=2020-08-17 |title=Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria |journal=eLife |language=en |volume=9 |doi=10.7554/eLife.58041 |issn=2050-084X |pmc=7470841 |pmid=32804083 |doi-access=free}}</ref> This enables cells to increase their oxidative capacity when substrates are abundant and prevents the electron transport chain from running empty and inducing the formation of [[reactive oxygen species]] (ROS) under substrate-limited conditions.<ref name="Nowinski-2020" /><ref name="Masud-2019" />

MtFAS is also thought to play a role as a mediator in [[Cell signaling|intracellular signaling]] due to its influence on the levels of bioactive lipids, such as [[Lysophospholipase|lysophospholipids]] and [[sphingolipid]]s.<ref>{{cite journal |vauthors=Clay HB, Parl AK, Mitchell SL, Singh L, Bell LN, Murdock DG |date=March 2016 |title=Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling |journal=PLOS ONE |volume=11 |issue=3 |article-number=e0151171 |bibcode=2016PLoSO..1151171C |doi=10.1371/journal.pone.0151171 |pmc=4786287 |pmid=26963735 |doi-access=free |veditors=Peterson J}}</ref>

===Uptake, storage and release of calcium ions===
[[File:Chondrocyte- calcium stain.jpg|right|thumb|400 px|[[Transmission electron microscope|Transmission]] [[Micrograph|electron micrograph]] of a [[chondrocyte]], stained for calcium, showing its nucleus (N) and mitochondria (M)]]
The concentrations of free calcium in the cell can regulate an array of reactions and is important for [[signal transduction]] in the cell. Mitochondria can transiently [[Calcium storage|store calcium]], a contributing process for the cell's homeostasis of calcium.<ref name="Santulli-2015c">{{cite journal | vauthors = Santulli G, Xie W, Reiken SR, Marks AR | title = Mitochondrial calcium overload is a key determinant in heart failure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 36 | pages = 11389–11394 | date = September 2015 | pmid = 26217001 | pmc = 4568687 | doi = 10.1073/pnas.1513047112 | doi-access = free | bibcode = 2015PNAS..11211389S }}</ref>
<ref name="Siegel-1999">{{cite book | veditors = Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD |title=Basic Neurochemistry |edition=6 |year=1999 |isbn=978-0-397-51820-3 |publisher=Lippincott Williams & Wilkins }}</ref> Their ability to rapidly take in calcium for later release makes them good "cytosolic buffers" for calcium.<ref name="Rossier-2006"/><ref>{{cite journal | vauthors = Brighton CT, Hunt RM | title = Mitochondrial calcium and its role in calcification. Histochemical localization of calcium in electron micrographs of the epiphyseal growth plate with K-pyroantimonate | journal = Clinical Orthopaedics and Related Research | volume = 100 | issue = 5 | pages = 406–416 | date = May 1974 | pmid = 4134194 | doi = 10.1097/00003086-197405000-00057 }}</ref><ref>
{{cite journal | vauthors = Brighton CT, Hunt RM | title = The role of mitochondria in growth plate calcification as demonstrated in a rachitic model | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 60 | issue = 5 | pages = 630–639 | date = July 1978 | pmid = 681381 | doi = 10.2106/00004623-197860050-00007 }}</ref> The endoplasmic reticulum (ER) is the most significant storage site of calcium,<ref name="Santulli-2015b"/> and there is a significant interplay between the mitochondrion and ER with regard to calcium.<ref>{{cite journal | vauthors = Pizzo P, Pozzan T | title = Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics | journal = Trends in Cell Biology | volume = 17 | issue = 10 | pages = 511–517 | date = October 2007 | pmid = 17851078 | doi = 10.1016/j.tcb.2007.07.011 }}</ref> The calcium is taken up into the [[mitochondrial matrix|matrix]] by the [[mitochondrial calcium uniporter]] on the [[inner mitochondrial membrane]].<ref name="Miller-1998">{{cite journal | vauthors = Miller RJ | title = Mitochondria - the Kraken wakes! | journal = Trends in Neurosciences | volume = 21 | issue = 3 | pages = 95–97 | date = March 1998 | pmid = 9530913 | doi = 10.1016/S0166-2236(97)01206-X }}</ref> It is primarily driven by the mitochondrial [[membrane potential]].<ref name="Siegel-1999"/> Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.<ref name="Miller-1998"/> This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of [[second messenger system]] proteins that can coordinate processes such as [[Synaptic vesicle|neurotransmitter release]] in nerve cells and release of [[hormone]]s in endocrine cells.<ref name="Santulli-2015a">{{cite journal | vauthors = Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR | title = Calcium release channel RyR2 regulates insulin release and glucose homeostasis | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1968–1978 | date = May 2015 | pmid = 25844899 | pmc = 4463204 | doi = 10.1172/JCI79273 }}</ref>

Ca{{sup|2+}} influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory [[bioenergetics]] by allowing the electrochemical potential across the membrane to transiently "pulse" from ΔΨ-dominated to pH-dominated, facilitating a reduction of [[oxidative stress]].<ref>{{cite journal | vauthors = Schwarzländer M, Logan DC, Johnston IG, Jones NS, Meyer AJ, Fricker MD, Sweetlove LJ | title = Pulsing of membrane potential in individual mitochondria: a stress-induced mechanism to regulate respiratory bioenergetics in Arabidopsis | journal = The Plant Cell | volume = 24 | issue = 3 | pages = 1188–1201 | date = March 2012 | pmid = 22395486 | pmc = 3336130 | doi = 10.1105/tpc.112.096438 | bibcode = 2012PlanC..24.1188S }}</ref> In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of [[isocitrate dehydrogenase]], one of the key regulatory enzymes of the [[Krebs cycle]].<ref>{{cite journal | vauthors = Ivannikov MV, Macleod GT | title = Mitochondrial free Ca²⁺ levels and their effects on energy metabolism in Drosophila motor nerve terminals | journal = Biophysical Journal | volume = 104 | issue = 11 | pages = 2353–2361 | date = June 2013 | pmid = 23746507 | pmc = 3672877 | doi = 10.1016/j.bpj.2013.03.064 | bibcode = 2013BpJ...104.2353I }}</ref>

===Cellular proliferation regulation===
The relationship between cellular proliferation and mitochondria has been investigated. Tumor cells require ample ATP to synthesize bioactive compounds such as [[lipid]]s, [[protein]]s, and [[nucleotide]]s for rapid proliferation.<ref name="Weinberg-2009">{{cite journal | vauthors = Weinberg F, Chandel NS | title = Mitochondrial metabolism and cancer | journal = Annals of the New York Academy of Sciences | volume = 1177 | issue = 1 | pages = 66–73 | date = October 2009 | pmid = 19845608 | doi = 10.1111/j.1749-6632.2009.05039.x | bibcode = 2009NYASA1177...66W }}</ref> The majority of ATP in tumor cells is generated via the [[oxidative phosphorylation]] pathway (OxPhos).<ref name="Moreno-Sánchez-2007">{{cite journal | vauthors = Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E | title = Energy metabolism in tumor cells | journal = The FEBS Journal | volume = 274 | issue = 6 | pages = 1393–1418 | date = March 2007 | pmid = 17302740 | doi = 10.1111/j.1742-4658.2007.05686.x }}</ref> Interference with OxPhos cause [[cell cycle]] arrest suggesting that mitochondria play a role in cell proliferation.<ref name="Moreno-Sánchez-2007"/> Mitochondrial ATP production is also vital for [[cell division]] and differentiation in infection<ref>{{cite journal | vauthors = Mistry JJ, Marlein CR, Moore JA, Hellmich C, Wojtowicz EE, Smith JG, Macaulay I, Sun Y, Morfakis A, Patterson A, Horton RH, Divekar D, Morris CJ, Haestier A, Di Palma F, Beraza N, Bowles KM, Rushworth SA | title = ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 49 | pages = 24610–24619 | date = December 2019 | pmid = 31727843 | pmc = 6900710 | doi = 10.1073/pnas.1913278116 | doi-access = free | bibcode = 2019PNAS..11624610M }}</ref> in addition to basic functions in the cell including the regulation of cell volume, solute [[concentration]], and cellular architecture.<ref name="Pedersen-1994">{{cite journal | vauthors = Pedersen PL | title = ATP synthase. The machine that makes ATP | journal = Current Biology | volume = 4 | issue = 12 | pages = 1138–1141 | date = December 1994 | pmid = 7704582 | doi = 10.1016/S0960-9822(00)00257-8 | bibcode = 1994CBio....4.1138P }}</ref><ref name="Pattappa-2011">{{cite journal | vauthors = Pattappa G, Heywood HK, de Bruijn JD, Lee DA | title = The metabolism of human mesenchymal stem cells during proliferation and differentiation | journal = Journal of Cellular Physiology | volume = 226 | issue = 10 | pages = 2562–2570 | date = October 2011 | pmid = 21792913 | doi = 10.1002/jcp.22605 }}</ref><ref name="Agarwal-2011">{{cite journal | vauthors = Agarwal B | title = A role for anions in ATP synthesis and its molecular mechanistic interpretation | journal = Journal of Bioenergetics and Biomembranes | volume = 43 | issue = 3 | pages = 299–310 | date = June 2011 | pmid = 21647635 | doi = 10.1007/s10863-011-9358-3 }}</ref> ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle.<ref name="Sweet-1999">{{cite journal | vauthors = Sweet S, Singh G | title = Changes in mitochondrial mass, membrane potential, and cellular adenosine triphosphate content during the cell cycle of human leukemic (HL-60) cells | journal = Journal of Cellular Physiology | volume = 180 | issue = 1 | pages = 91–96 | date = July 1999 | pmid = 10362021 | doi = 10.1002/(SICI)1097-4652(199907)180:1<91::AID-JCP10>3.0.CO;2-6 }}</ref> ATP's role in the basic functions of the cell make the [[cell cycle]] sensitive to changes in the availability of mitochondrial derived ATP.<ref name="Sweet-1999"/> The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation.<ref name="Sweet-1999"/> Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division.<ref name="McBride-2006"/>

=== Programmed cell death and innate immunity ===
{{Further|Programmed cell death#Intrinsic Pathway}}

[[Programmed cell death]] (PCD) is crucial for various physiological functions, including organ development and cellular homeostasis. It serves as an intrinsic mechanism to prevent [[malignant transformation]] and plays a fundamental role in [[Immune system|immunity]] by aiding in antiviral defense, pathogen elimination, inflammation, and immune cell recruitment.<ref>{{cite journal | vauthors = Riera Romo M | title = Cell death as part of innate immunity: Cause or consequence? | journal = Immunology | volume = 163 | issue = 4 | pages = 399–415 | date = August 2021 | pmid = 33682112 | pmc = 8274179 | doi = 10.1111/imm.13325 }}</ref>

Mitochondria have long been recognized for their central role in the [[Apoptosis#Intrinsic pathway|intrinsic pathway]] of [[apoptosis]], a form of PCD.<ref>{{cite journal | vauthors = Green DR | title = Apoptotic pathways: the roads to ruin | journal = Cell | volume = 94 | issue = 6 | pages = 695–698 | date = September 1998 | pmid = 9753316 | doi = 10.1016/S0092-8674(00)81728-6 | doi-access = free }}</ref> In recent decades, they have also been identified as a signalling hub for much of the [[innate immune system]].<ref name="Bahat-2021">{{cite journal | vauthors = Bahat A, MacVicar T, Langer T | title = Metabolism and Innate Immunity Meet at the Mitochondria | language = English | journal = Frontiers in Cell and Developmental Biology | volume = 9 | article-number = 720490 | date = 2021-07-27 | pmid = 34386501 | doi = 10.3389/fcell.2021.720490 | doi-access = free | pmc = 8353256 }}</ref> The [[Symbiogenesis|endosymbiotic origin]] of mitochondria distinguishes them from other cellular components, and the exposure of mitochondrial elements to the [[cytosol]] can trigger the same pathways as infection markers. These pathways lead to [[apoptosis]], [[autophagy]], or the induction of proinflammatory genes.<ref name="Murphy-2024">{{cite journal | vauthors = Murphy MP, O'Neill LA | title = A break in mitochondrial endosymbiosis as a basis for inflammatory diseases | journal = Nature | volume = 626 | issue = 7998 | pages = 271–279 | date = February 2024 | pmid = 38326590 | doi = 10.1038/s41586-023-06866-z | bibcode = 2024Natur.626..271M | url = https://www.repository.cam.ac.uk/handle/1810/364692 }}</ref><ref name="Bahat-2021" />

Mitochondria contribute to apoptosis by releasing [[Cytochrome c|cytochrome ''c'']], which directly induces the formation of [[apoptosome]]s. Additionally, they are a source of various [[damage-associated molecular pattern]]s (DAMPs). These DAMPs are often recognised by the same [[Pattern recognition receptor|pattern-recognition receptors]] (PRRs) that respond to [[pathogen-associated molecular pattern]]s (PAMPs) during infections.{{refn|{{cite journal | vauthors = Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P | title = Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation | journal = Trends in Immunology | volume = 32 | issue = 4 | pages = 157–164 | date = April 2011 | pmid = 21334975 | doi = 10.1016/j.it.2011.01.005 | url = https://lirias.kuleuven.be/bitstream/123456789/632510/2/Krysko%20et%20al%20_21-09-10.doc | url-access = subscription }}; cited in<ref name="Murphy-2024" />}} For example, mitochondrial mtDNA resembles bacterial DNA due to its lack of [[CpG site|CpG]] methylation and can be detected by [[Toll-like receptor 9]] and [[CGAS–STING cytosolic DNA sensing pathway|cGAS]].{{refn|{{cite journal | vauthors = Riley JS, Tait SW | title = Mitochondrial DNA in inflammation and immunity | journal = EMBO Reports | volume = 21 | issue = 4 | article-number = e49799 | date = April 2020 | pmid = 32202065 | pmc = 7132203 | doi = 10.15252/embr.201949799 }}; cited in<ref name="Murphy-2024" />}} [[DsRNA|Double-stranded RNA]]  (dsRNA), produced due to bidirectional mitochondrial transcription, can activate viral sensing pathways through [[RIG-I-like receptor]]s.{{refn|{{cite journal | vauthors = Seth RB, Sun L, Ea CK, Chen ZJ | title = Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3 | journal = Cell | volume = 122 | issue = 5 | pages = 669–682 | date = September 2005 | pmid = 16125763 | doi = 10.1016/j.cell.2005.08.012 }}; cited in<ref name="Murphy-2024" />}} Additionally, the ''N''-formylation of [[Human mitochondrial genetics|mitochondrial proteins]], similar to that of bacterial proteins, can be recognized by [[formyl peptide receptor]]s.{{refn|{{cite journal | vauthors = Dorward DA, Lucas CD, Doherty MK, Chapman GB, Scholefield EJ, Conway Morris A, Felton JM, Kipari T, Humphries DC, Robb CT, Simpson AJ, Whitfield PD, Haslett C, Dhaliwal K, Rossi AG | title = Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome | journal = Thorax | volume = 72 | issue = 10 | pages = 928–936 | date = October 2017 | pmid = 28469031 | pmc = 5738532 | doi = 10.1136/thoraxjnl-2017-210030 }}; cited in<ref name="Murphy-2024" />}}{{refn|{{cite journal | vauthors = Cai N, Gomez-Duran A, Yonova-Doing E, Kundu K, Burgess AI, Golder ZJ, Calabrese C, Bonder MJ, Camacho M, Lawson RA, Li L, Williams-Gray CH, Di Angelantonio E, Roberts DJ, Watkins NA, Ouwehand WH, Butterworth AS, Stewart ID, Pietzner M, Wareham NJ, Langenberg C, Danesh J, Walter K, Rothwell PM, Howson JM, Stegle O, Chinnery PF, Soranzo N | title = Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases | journal = Nature Medicine | volume = 27 | issue = 9 | pages = 1564–1575 | date = September 2021 | pmid = 34426706 | doi = 10.1038/s41591-021-01441-3 | first14 = Emanuele | first15 = David J. | hdl = 10261/249231 | hdl-access = free }}; cited in<ref name="Murphy-2024" />}}

Normally, these mitochondrial components are sequestered from the rest of the cell but are released following mitochondrial membrane permeabilization during apoptosis or passively after mitochondrial damage. However, mitochondria also play an active role in innate immunity, releasing mtDNA in response to metabolic cues.<ref name="Bahat-2021" /> Mitochondria are also the [[Subcellular localization|localization site]] for immune and apoptosis regulatory proteins, such as [[Apoptosis regulator BAX|BAX]], [[Mitochondrial antiviral-signaling protein|MAVS]] (located on the [[Mitochondrion#Outer membrane|outer membrane]]), and [[NLRX1]] (found in the [[Mitochondrion#Matrix|matrix]]). These proteins are modulated by the mitochondrial metabolic status and mitochondrial dynamics.<ref name="Bahat-2021" />{{refn|{{cite journal | vauthors = Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai SW, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK | title = Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS | journal = Cell | volume = 178 | issue = 1 | pages = 176–189.e15 | date = June 2019 | pmid = 31155231 | pmc = 6625351 | doi = 10.1016/j.cell.2019.05.003 }}; cited in<ref name="Bahat-2021" />}}{{refn|{{cite journal | vauthors = Pourcelot M, Arnoult D | title = Mitochondrial dynamics and the innate antiviral immune response | journal = The FEBS Journal | volume = 281 | issue = 17 | pages = 3791–3802 | date = September 2014 | pmid = 25051991 | doi = 10.1111/febs.12940 }}; cited in<ref name="Bahat-2021" />}}

=== Donation ===
Some cells donate mitochondria to other cells. Such donations occur in multiple cell types, in organisms such as yeast, molluscs, and rodents. Mitochondrial donation was first observed in 2006. {{As of|2025|post=,}} it had not been observed in humans ''[[in vivo]]''. Donations may occur to help damaged cells, trigger tissue repair or the immune system, or to power distressed cells.<ref name="Conroy-2025">{{Cite journal |last=Conroy |first=Gemma |date=2025-04-08 |title=Cells are swapping their mitochondria. What does this mean for our health? |url=https://www.nature.com/articles/d41586-025-01064-5 |journal=Nature |language=en |volume=640 |issue=8058 |pages=302–304 |doi=10.1038/d41586-025-01064-5 |pmid=40200117 |issn=1476-4687|url-access=subscription }}</ref>

Researchers cultured human mitochondria-free lung cancer cells with stem cells. The stem cells ejected mitochondria, which were absorbed by the lung cells. The lung cells then recovered their ability to divide and metabolize glucose. Mitochondria were then detected moving among lung, heart, brain, fat, bone, and other cells. Research has not identified how a cell indicates that it needs mitochondrial assistance or how other cells read those indicators.<ref name="Conroy-2025" />

Various purposes have been observed to explain such donations. These include:<ref name="Conroy-2025" />

* Restore function and extending lifespans of damaged cells<ref>{{Cite journal |last1=Spees |first1=Jeffrey L. |last2=Olson |first2=Scott D. |last3=Whitney |first3=Mandolin J. |last4=Prockop |first4=Darwin J. |date=2006-01-31 |title=Mitochondrial transfer between cells can rescue aerobic respiration |journal=Proceedings of the National Academy of Sciences |volume=103 |issue=5 |pages=1283–1288 |doi=10.1073/pnas.0510511103 |doi-access=free |pmc=1345715 |pmid=16432190|bibcode=2006PNAS..103.1283S }}</ref><ref>{{Cite journal |last1=Ahmad |first1=Tanveer |last2=Mukherjee |first2=Shravani |last3=Pattnaik |first3=Bijay |last4=Kumar |first4=Manish |last5=Singh |first5=Suchita |last6=Kumar |first6=Manish |last7=Rehman |first7=Rakhshinda |last8=Tiwari |first8=Brijendra K |last9=Jha |first9=Kumar A |last10=Barhanpurkar |first10=Amruta P |last11=Wani |first11=Mohan R |last12=Roy |first12=Soumya S |last13=Mabalirajan |first13=Ulaganathan |last14=Ghosh |first14=Balaram |last15=Agrawal |first15=Anurag |date=January 2014 |title=Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy |journal=The EMBO Journal |volume=33 |issue=9 |pages=994–1010 |doi=10.1002/embj.201386030 |pmid=24431222 |pmc=4193933 |issn=0261-4189}}</ref><ref>{{Cite journal |last1=Hayakawa |first1=Kazuhide |last2=Esposito |first2=Elga |last3=Wang |first3=Xiaohua |last4=Terasaki |first4=Yasukazu |last5=Liu |first5=Yi |last6=Xing |first6=Changhong |last7=Ji |first7=Xunming |last8=Lo |first8=Eng H. |date=July 2016 |title=Transfer of mitochondria from astrocytes to neurons after stroke |journal=Nature |language=en |volume=535 |issue=7613 |pages=551–555 |doi=10.1038/nature18928 |pmid=27466127 |pmc=4968589 |bibcode=2016Natur.535..551H |issn=1476-4687}}</ref>
* Endothelial cell donation to cancer cells can increase chemoresistance<ref>{{Cite journal |last1=Pasquier |first1=Jennifer |last2=Guerrouahen |first2=Bella S. |last3=Al Thawadi |first3=Hamda |last4=Ghiabi |first4=Pegah |last5=Maleki |first5=Mahtab |last6=Abu-Kaoud |first6=Nadine |last7=Jacob |first7=Arthur |last8=Mirshahi |first8=Massoud |last9=Galas |first9=Ludovic |last10=Rafii |first10=Shahin |last11=Le Foll |first11=Frank |last12=Rafii |first12=Arash |date=2013-04-10 |title=Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance |journal=Journal of Translational Medicine |volume=11 |issue=1 |page=94 |doi=10.1186/1479-5876-11-94 |doi-access=free |issn=1479-5876 |pmc=3668949 |pmid=23574623}}</ref> or tumorigenic potential.<ref>{{Cite journal |last1=Tan |first1=An S. |last2=Baty |first2=James W. |last3=Dong |first3=Lan-Feng |last4=Bezawork-Geleta |first4=Ayenachew |last5=Endaya |first5=Berwini |last6=Goodwin |first6=Jacob |last7=Bajzikova |first7=Martina |last8=Kovarova |first8=Jaromira |last9=Peterka |first9=Martin |last10=Yan |first10=Bing |last11=Pesdar |first11=Elham Alizadeh |last12=Sobol |first12=Margarita |last13=Filimonenko |first13=Anatolyj |last14=Stuart |first14=Shani |last15=Vondrusova |first15=Magdalena |date=2015-01-06 |title=Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA |journal=Cell Metabolism |volume=21 |issue=1 |pages=81–94 |doi=10.1016/j.cmet.2014.12.003 |issn=1932-7420 |pmid=25565207}}</ref>
* Following acute lung injury, stromal cells can donate mitochondria to lung cells, which in turn distributed ATP (fuel) to nearby cells that did not receive mitochondria.<ref>{{Cite journal |last1=Islam |first1=Mohammad Naimul |last2=Das |first2=Shonit R. |last3=Emin |first3=Memet T. |last4=Wei |first4=Michelle |last5=Sun |first5=Li |last6=Westphalen |first6=Kristin |last7=Rowlands |first7=David J. |last8=Quadri |first8=Sadiqa K. |last9=Bhattacharya |first9=Sunita |last10=Bhattacharya |first10=Jahar |date=May 2012 |title=Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury |journal=Nature Medicine |language=en |volume=18 |issue=5 |pages=759–765 |doi=10.1038/nm.2736 |pmid=22504485 |pmc=3727429 |issn=1546-170X}}</ref>
* Platelets can donate mitochondria to stem cells which then release molecules that aid in blood vessel formation, which accelerates wound healing. Bone cell donations had a similar effect.
* Maintain the blood-brain barrier
* Maintain macrophage function when their metabolism is disrupted
* Reduce inflammatory response, particularly when donated to T cells. Stem cells cultured from rheumatoid arthritis patients donated fewer mitochondria to T cells than do those from others.

Extracellular mitochondria use multiple modes of transport:<ref name="Conroy-2025" />

** tunnelling nanotubes that temporarily connect cells to transport various cargo<ref>{{Cite journal |last1=Wang |first1=X. |last2=Gerdes |first2=H.-H. |date=July 2015 |title=Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells |url=https://www.nature.com/articles/cdd2014211 |journal=Cell Death & Differentiation |language=en |volume=22 |issue=7 |pages=1181–1191 |doi=10.1038/cdd.2014.211 |issn=1476-5403|hdl=1956/10814 |hdl-access=free }}</ref>
** passengers on [[Vesicle (biology and chemistry)|vesicles]] 
** free-floating (typically in blood)
** cell contact/fusion

=== Additional functions ===
Mitochondria play a central role in many other [[metabolism|metabolic]] tasks, such as:
* Signaling through mitochondrial [[reactive oxygen species]]<ref name="Li-2013">{{cite journal | vauthors = Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF | title = Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers | journal = Journal of Hematology & Oncology | volume = 6 | issue = 19 | article-number = 19 | date = February 2013 | pmid = 23442817 | pmc = 3599349 | doi = 10.1186/1756-8722-6-19 | doi-access = free }}</ref>
* Regulation of the [[membrane potential]]<ref name="Voet-2006"/>
* Calcium signaling (including calcium-evoked apoptosis)<ref>{{cite journal | vauthors = Hajnóczky G, Csordás G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, Yi M | title = Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis | journal = Cell Calcium | volume = 40 | issue = 5–6 | pages = 553–560 | year = 2006 | pmid = 17074387 | pmc = 2692319 | doi = 10.1016/j.ceca.2006.08.016 }}</ref>
* Regulation of cellular [[metabolism]]<ref name="McBride-2006">{{cite journal | vauthors = McBride HM, Neuspiel M, Wasiak S | title = Mitochondria: more than just a powerhouse | journal = Current Biology | volume = 16 | issue = 14 | pages = R551–R560 | date = July 2006 | pmid = 16860735 | doi = 10.1016/j.cub.2006.06.054 | doi-access = free | bibcode = 2006CBio...16.R551M }}</ref>
* Certain [[heme]] synthesis reactions<ref>{{cite journal | vauthors = Oh-hama T | title = Evolutionary consideration on 5-aminolevulinate synthase in nature | journal = Origins of Life and Evolution of the Biosphere | volume = 27 | issue = 4 | pages = 405–412 | date = August 1997 | pmid = 9249985 | doi = 10.1023/A:1006583601341 | bibcode = 1997OLEB...27..405O }}</ref> (see also: ''[[Porphyrin]]'')
* [[Steroid]] synthesis<ref name="Rossier-2006">{{cite journal | vauthors = Rossier MF | title = T channels and steroid biosynthesis: in search of a link with mitochondria | journal = Cell Calcium | volume = 40 | issue = 2 | pages = 155–164 | date = August 2006 | pmid = 16759697 | doi = 10.1016/j.ceca.2006.04.020 }}</ref>
* Hormonal signaling<ref>{{cite journal | vauthors = Klinge CM | title = Estrogenic control of mitochondrial function and biogenesis | journal = Journal of Cellular Biochemistry | volume = 105 | issue = 6 | pages = 1342–1351 | date = December 2008 | pmid = 18846505 | pmc = 2593138 | doi = 10.1002/jcb.21936 }}</ref> – mitochondria are sensitive and responsive to hormones, in part by the action of mitochondrial estrogen receptors (mtERs). These receptors have been found in various tissues and cell types, including brain<ref>{{cite journal | vauthors = Alvarez-Delgado C, Mendoza-Rodríguez CA, Picazo O, Cerbón M | title = Different expression of alpha and beta mitochondrial estrogen receptors in the aging rat brain: interaction with respiratory complex V | journal = Experimental Gerontology | volume = 45 | issue = 7–8 | pages = 580–585 | date = August 2010 | pmid = 20096765 | doi = 10.1016/j.exger.2010.01.015 }}</ref> and heart<ref>{{cite journal | vauthors = Pavón N, Martínez-Abundis E, Hernández L, Gallardo-Pérez JC, Alvarez-Delgado C, Cerbón M, Pérez-Torres I, Aranda A, Chávez E | title = Sexual hormones: effects on cardiac and mitochondrial activity after ischemia-reperfusion in adult rats. Gender difference | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 132 | issue = 1–2 | pages = 135–146 | date = October 2012 | pmid = 22609314 | doi = 10.1016/j.jsbmb.2012.05.003 }}</ref>
* Development and function of immune cells<ref>{{cite journal | vauthors = Breda CN, Davanzo GG, Basso PJ, Saraiva Câmara NO, Moraes-Vieira PM | title = Mitochondria as central hub of the immune system | journal = Redox Biology | volume = 26 | article-number = 101255 | date = September 2019 | pmid = 31247505 | pmc = 6598836 | doi = 10.1016/j.redox.2019.101255 }}</ref>
* Neuronal mitochondria also contribute to cellular quality control by reporting neuronal status towards microglia through specialised somatic-junctions.<ref name="Cserép-2020"/>
* Mitochondria of developing neurons contribute to intercellular signaling towards [[microglia]], which communication is indispensable for proper regulation of brain development.<ref>{{cite journal | vauthors = Cserép C, Schwarcz AD, Pósfai B, László ZI, Kellermayer A, Környei Z, Kisfali M, Nyerges M, Lele Z, Katona I | title = Microglial control of neuronal development via somatic purinergic junctions | journal = Cell Reports | volume = 40 | issue = 12 | article-number = 111369 | date = September 2022 | pmid = 36130488 | pmc = 9513806 | doi = 10.1016/j.celrep.2022.111369 }}</ref>

Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in [[liver cell]]s contain enzymes that allow them to detoxify [[ammonia]], a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in [[mitochondrial disease]]s.

Mitochondrial proteins (proteins transcribed from mitochondrial DNA) vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified from [[heart|cardiac]] mitochondria,<ref>{{cite journal | vauthors = Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS | title = Characterization of the human heart mitochondrial proteome | journal = Nature Biotechnology | volume = 21 | issue = 3 | pages = 281–286 | date = March 2003 | pmid = 12592411 | doi = 10.1038/nbt793 }}</ref> whereas in [[Murinae|rats]], 940 proteins have been reported.<ref>{{cite journal | vauthors = Zhang J, Li X, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Liem DA, Yang JI, Korge P, Honda H, Weiss JN, Apweiler R, Ping P | title = Systematic characterization of the murine mitochondrial proteome using functionally validated cardiac mitochondria | journal = Proteomics | volume = 8 | issue = 8 | pages = 1564–1575 | date = April 2008 | pmid = 18348319 | pmc = 2799225 | doi = 10.1002/pmic.200700851 }}</ref> The mitochondrial [[proteome]] is thought to be dynamically regulated.<ref>{{cite journal | vauthors = Zhang J, Liem DA, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Korge P, Drews O, Maclellan WR, Honda H, Weiss JN, Apweiler R, Ping P | title = Altered proteome biology of cardiac mitochondria under stress conditions | journal = Journal of Proteome Research | volume = 7 | issue = 6 | pages = 2204–2214 | date = June 2008 | pmid = 18484766 | pmc = 3805274 | doi = 10.1021/pr070371f }}</ref>

==Organization and distribution==
[[File:HeLa mtGFP.tif|thumb|Typical mitochondrial network (green) in two human cells ([[HeLa cells]])]]
Mitochondria (or related structures) are found in all [[eukaryote]]s (except the [[Oxymonad]] ''[[Monocercomonoides]]'').<ref name="Karnkowska-2016">{{cite journal | vauthors = Karnkowska A, Vacek V, Zubáčová Z, Treitli SC, Petrželková R, Eme L, Novák L, Žárský V, Barlow LD, Herman EK, Soukal P, Hroudová M, Doležal P, Stairs CW, Roger AJ, Eliáš M, Dacks JB, Vlček Č, Hampl V | title = A Eukaryote without a Mitochondrial Organelle | journal = Current Biology | volume = 26 | issue = 10 | pages = 1274–1284 | date = May 2016 | pmid = 27185558 | doi = 10.1016/j.cub.2016.03.053 | doi-access = free | bibcode = 2016CBio...26.1274K }}</ref> Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo [[mitochondrial fission|fission]] and [[mitochondrial fusion|fusion]]. The population of all the mitochondria of a given cell constitutes the '''chondriome'''.<ref name="Logan-2010">{{cite journal | vauthors = Logan DC | title = Mitochondrial fusion, division and positioning in plants | journal = Biochemical Society Transactions | volume = 38 | issue = 3 | pages = 789–795 | date = June 2010 | pmid = 20491666 | doi = 10.1042/bst0380789 }}</ref> Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms, while human liver cells have about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume.<ref name="Alberts-2005"/> The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential,<ref>{{cite journal | vauthors = das Neves RP, Jones NS, Andreu L, Gupta R, Enver T, Iborra FJ | title = Connecting variability in global transcription rate to mitochondrial variability | journal = PLOS Biology | volume = 8 | issue = 12 | article-number = e1000560 | date = December 2010 | pmid = 21179497 | pmc = 3001896 | doi = 10.1371/journal.pbio.1000560 | veditors = Weissman JS | doi-access = free }}</ref> with differences arising from sources including uneven partitioning at cell division, leading to [[cellular noise|extrinsic differences]] in ATP levels and downstream cellular processes.<ref>{{cite journal | vauthors = Johnston IG, Gaal B, Neves RP, Enver T, Iborra FJ, Jones NS | title = Mitochondrial variability as a source of extrinsic cellular noise | journal = PLOS Computational Biology | volume = 8 | issue = 3 | article-number = e1002416 | year = 2012 | pmid = 22412363 | pmc = 3297557 | doi = 10.1371/journal.pcbi.1002416 | veditors = Haugh JM | doi-access = free | arxiv = 1107.4499 | bibcode = 2012PLSCB...8E2416J }}</ref> The mitochondria can be found nestled between [[myofibril]]s of [[muscle]] or wrapped around the [[sperm]] [[flagellum]].<ref name="Alberts-2005"/> Often, they form a complex 3D branching network inside the cell with the [[cytoskeleton]]. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well:<ref>{{cite journal | vauthors = Rappaport L, Oliviero P, Samuel JL | title = Cytoskeleton and mitochondrial morphology and function | journal = Molecular and Cellular Biochemistry | volume = 184 | issue = 1–2 | pages = 101–105 | date = July 1998 | pmid = 9746315 | doi = 10.1023/A:1006843113166 }}</ref> different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages.<ref>{{cite journal | vauthors = Hoitzing H, Johnston IG, Jones NS | title = What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research | journal = BioEssays | volume = 37 | issue = 6 | pages = 687–700 | date = June 2015 | pmid = 25847815 | pmc = 4672710 | doi = 10.1002/bies.201400188 }}</ref> Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the [[endoplasmic reticulum]].<ref>{{cite journal | vauthors = Soltys BJ, Gupta RS | title = Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules--a quadruple fluorescence labeling study | journal = Biochemistry and Cell Biology | volume = 70 | issue = 10–11 | pages = 1174–1186 | year = 1992 | pmid = 1363623 | doi = 10.1139/o92-163 }}</ref> Recent evidence suggests that [[vimentin]], one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.<ref>{{cite journal | vauthors = Tang HL, Lung HL, Wu KC, Le AH, Tang HM, Fung MC | title = Vimentin supports mitochondrial morphology and organization | journal = The Biochemical Journal | volume = 410 | issue = 1 | pages = 141–146 | date = February 2008 | pmid = 17983357 | doi = 10.1042/BJ20071072 }}</ref>

===Mitochondria-associated ER membrane (MAM)===
{{Main|Mitochondria associated membranes}}

The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and [[homeostasis]]. Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.<ref name="Rizzuto-2009">{{cite journal | vauthors = Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P | title = Ca(2+) transfer from the ER to mitochondria: when, how and why | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1787 | issue = 11 | pages = 1342–1351 | date = November 2009 | pmid = 19341702 | pmc = 2730423 | doi = 10.1016/j.bbabio.2009.03.015 }}</ref> Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with [[fluorescence microscopy]].<ref name="Rizzuto-2009"/> Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25&nbsp;nm and held together by protein tethering complexes.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009">{{cite journal | vauthors = Hayashi T, Rizzuto R, Hajnoczky G, Su TP | title = MAM: more than just a housekeeper | journal = Trends in Cell Biology | volume = 19 | issue = 2 | pages = 81–88 | date = February 2009 | pmid = 19144519 | pmc = 2750097 | doi = 10.1016/j.tcb.2008.12.002 }}</ref><ref name="de Brito-2010">{{cite journal | vauthors = de Brito OM, Scorrano L | title = An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship | journal = The EMBO Journal | volume = 29 | issue = 16 | pages = 2715–2723 | date = August 2010 | pmid = 20717141 | pmc = 2924651 | doi = 10.1038/emboj.2010.177 }}</ref>

Purified MAM from subcellular fractionation is enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca{{sup|2+}} signaling.<ref name="Rizzuto-2009"/><ref name="de Brito-2010"/> These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.

====Phospholipid transfer====
The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face.<ref name="Vance-1996">{{cite journal | vauthors = Vance JE, Shiao YJ | title = Intracellular trafficking of phospholipids: import of phosphatidylserine into mitochondria | journal = Anticancer Research | volume = 16 | issue = 3B | pages = 1333–1339 | year = 1996 | pmid = 8694499 }}</ref><ref name="Lebiedzinska-2009">{{cite journal | vauthors = Lebiedzinska M, Szabadkai G, Jones AW, Duszynski J, Wieckowski MR | title = Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles | journal = The International Journal of Biochemistry & Cell Biology | volume = 41 | issue = 10 | pages = 1805–1816 | date = October 2009 | pmid = 19703651 | doi = 10.1016/j.biocel.2009.02.017 }}</ref> Because mitochondria are dynamic organelles constantly undergoing [[mitochondrial fission|fission]] and [[mitochondrial fusion|fusion]] events, they require a constant and well-regulated supply of phospholipids for membrane integrity.<ref name="Twig-2008">{{cite journal | vauthors = Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS | title = Fission and selective fusion govern mitochondrial segregation and elimination by autophagy | journal = The EMBO Journal | volume = 27 | issue = 2 | pages = 433–446 | date = January 2008 | pmid = 18200046 | pmc = 2234339 | doi = 10.1038/sj.emboj.7601963 }}</ref><ref name="Osman-2011">{{cite journal | vauthors = Osman C, Voelker DR, Langer T | title = Making heads or tails of phospholipids in mitochondria | journal = The Journal of Cell Biology | volume = 192 | issue = 1 | pages = 7–16 | date = January 2011 | pmid = 21220505 | pmc = 3019561 | doi = 10.1083/jcb.201006159 }}</ref> But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.<ref name="Lebiedzinska-2009"/><ref name="Osman-2011"/>

Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles.<ref name="Vance-1996"/> In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers.<ref name="Osman-2011"/> Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP.<ref name="Osman-2011"/> Instead, in yeast, it has been shown to be dependent on a [[Protein complex|multiprotein]] tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the [[activation energy|energy barrier]] for [[lipid]] flipping.<ref name="Osman-2011"/><ref name="Kornmann-2009">{{cite journal | vauthors = Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P | title = An ER-mitochondria tethering complex revealed by a synthetic biology screen | journal = Science | volume = 325 | issue = 5939 | pages = 477–481 | date = July 2009 | pmid = 19556461 | pmc = 2933203 | doi = 10.1126/science.1175088 | bibcode = 2009Sci...325..477K }}</ref>

The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to [[very-low-density lipoprotein]], or VLDL, assembly and secretion.<ref name="Lebiedzinska-2009"/><ref name="Rusiñol-1994">{{cite journal | vauthors = Rusiñol AE, Cui Z, Chen MH, Vance JE | title = A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins | journal = The Journal of Biological Chemistry | volume = 269 | issue = 44 | pages = 27494–27502 | date = November 1994 | pmid = 7961664 | doi = 10.1016/S0021-9258(18)47012-3 | doi-access = free }}</ref> The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

====Calcium signaling====
A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca{{sup|2+}} channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca{{sup|2+}} flux.<ref name="Rizzuto-2009"/><ref name="Santulli-2015b">{{cite journal | vauthors = Santulli G, Marks AR | title = Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging | journal = Current Molecular Pharmacology | volume = 8 | issue = 2 | pages = 206–222 | date = 2015 | pmid = 25966694 | doi = 10.2174/1874467208666150507105105 }}</ref> But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca{{sup|2+}} microdomains at contact points that facilitate efficient Ca{{sup|2+}} transmission from the ER to the mitochondria.<ref name="Rizzuto-2009"/> Transmission occurs in response to so-called "Ca{{sup|2+}} puffs" generated by spontaneous clustering and activation of [[IP3R]], a canonical ER membrane Ca{{sup|2+}} channel.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009"/>

The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca{{sup|2+}} waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca{{sup|2+}} by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca{{sup|2+}} exposure, the MAM often serves as a firewall that essentially buffers Ca{{sup|2+}} puffs by acting as a sink into which free ions released into the cytosol can be funneled.<ref name="Rizzuto-2009"/><ref name="Kopach-2008">{{cite journal | vauthors = Kopach O, Kruglikov I, Pivneva T, Voitenko N, Fedirko N | title = Functional coupling between ryanodine receptors, mitochondria and Ca(2+) ATPases in rat submandibular acinar cells | journal = Cell Calcium | volume = 43 | issue = 5 | pages = 469–481 | date = May 2008 | pmid = 17889347 | doi = 10.1016/j.ceca.2007.08.001 }}</ref><ref name="Csordás-2001">{{cite journal | vauthors = Csordás G, Hajnóczky G | title = Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria | journal = Cell Calcium | volume = 29 | issue = 4 | pages = 249–262 | date = April 2001 | pmid = 11243933 | doi = 10.1054/ceca.2000.0191 }}</ref> This Ca{{sup|2+}} tunneling occurs through the low-affinity Ca{{sup|2+}} receptor [[VDAC1]], which recently has been shown to be physically [[tether (cell biology)|tethered]] to the IP3R clusters on the ER membrane and enriched at the MAM.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009"/><ref name="Decuypere-2011">{{cite journal | vauthors = Decuypere JP, Monaco G, Bultynck G, Missiaen L, De Smedt H, Parys JB | title = The IP(3) receptor-mitochondria connection in apoptosis and autophagy | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1813 | issue = 5 | pages = 1003–1013 | date = May 2011 | pmid = 21146562 | doi = 10.1016/j.bbamcr.2010.11.023 | doi-access =}}</ref> The ability of mitochondria to serve as a Ca{{sup|2+}} sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process.<ref name="Decuypere-2011"/> Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

But transmission of Ca{{sup|2+}} is not unidirectional; rather, it is a two-way street.<ref name="Santulli-2015b"/> The properties of the Ca{{sup|2+}} pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca{{sup|2+}} by the MAM allows for [[spatio-temporal pattern]]ing of Ca{{sup|2+}} signaling because Ca{{sup|2+}} alters IP3R activity in a biphasic manner.<ref name="Rizzuto-2009"/> [[SERCA]] is likewise affected by mitochondrial feedback: uptake of Ca{{sup|2+}} by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca{{sup|2+}} for continued Ca{{sup|2+}} efflux at the MAM.<ref name="Kopach-2008"/><ref name="Decuypere-2011"/> Thus, the MAM is not a passive buffer for Ca{{sup|2+}} puffs; rather it helps modulate further Ca{{sup|2+}} signaling through feedback loops that affect ER dynamics.

Regulating ER release of Ca{{sup|2+}} at the MAM is especially critical because only a certain window of Ca{{sup|2+}} uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca{{sup|2+}} signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.<ref name="Diercks-2017">{{cite journal | vauthors = Diercks BP, Fliegert R, Guse AH | title = Mag-Fluo4 in T cells: Imaging of intra-organelle free Ca<sup>2+</sup> concentrations | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1864 | issue = 6 | pages = 977–986 | date = June 2017 | pmid = 27913206 | doi = 10.1016/j.bbamcr.2016.11.026 | doi-access = free }}</ref><ref name="Hajnóczky-2011">{{cite journal | vauthors = Hajnóczky G, Csordás G, Yi M | title = Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria | journal = Cell Calcium | volume = 32 | issue = 5–6 | pages = 363–377 | year = 2011 | pmid = 12543096 | doi = 10.1016/S0143416002001872 }}</ref> However, once Ca{{sup|2+}} signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism.<ref name="Rizzuto-2009"/> Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca{{sup|2+}} filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.<ref name="Rizzuto-2009"/> Given the need for such fine regulation of Ca{{sup|2+}} signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca{{sup|2+}} has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.<ref name="Decuypere-2011"/>

====Molecular basis for tethering====
Recent advances in the identification of the [[tether (cell biology)|tethers]] between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer.<ref name="Osman-2011"/> However, a [[Homology (biology)|homologue]] of the ERMES complex has not yet been identified in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in [[Mitochondrial fission|fission]] and [[Mitochondrial fusion|fusion]] events between individual mitochondria.<ref name="Rizzuto-2009"/> [[Glucose]]-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca{{sup|2+}} channels VDAC and IP3R for efficient Ca{{sup|2+}} transmission at the MAM.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009"/> Another potential tether is [[Sigma-1 receptor|Sigma-1R]], a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response.<ref>{{cite journal | vauthors = Marriott KS, Prasad M, Thapliyal V, Bose HS | title = σ-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 343 | issue = 3 | pages = 578–586 | date = December 2012 | pmid = 22923735 | pmc = 3500540 | doi = 10.1124/jpet.112.198168 }}</ref><ref>{{cite journal | vauthors = Hayashi T, Su TP | title = Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival | journal = Cell | volume = 131 | issue = 3 | pages = 596–610 | date = November 2007 | pmid = 17981125 | doi = 10.1016/j.cell.2007.08.036 | doi-access = free }}</ref>

[[File:ERMES.png|thumb|alt=ERMES tethering complex.|Model of the yeast multimeric tethering complex, ERMES]]

====Perspective====
The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology. Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and [[homeostasis]]. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell.<ref name="Csordás-2018">{{cite journal | vauthors = Csordás G, Weaver D, Hajnóczky G | title = Endoplasmic Reticulum-Mitochondrial Contactology: Structure and Signaling Functions | journal = Trends in Cell Biology | volume = 28 | issue = 7 | pages = 523–540 | date = July 2018 | pmid = 29588129 | pmc = 6005738 | doi = 10.1016/j.tcb.2018.02.009 }}</ref> Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes. Recently it has also been shown, that mitochondria and MAM-s in neurons are anchored to specialised intercellular communication sites (so called somatic-junctions). [[Microglia]]l processes monitor and protect neuronal functions at these sites, and MAM-s are supposed to have an important role in this type of cellular quality-control.<ref name="Cserép-2020">{{cite journal | vauthors = Cserép C, Pósfai B, Lénárt N, Fekete R, László ZI, Lele Z, Orsolits B, Molnár G, Heindl S, Schwarcz AD, Ujvári K, Környei Z, Tóth K, Szabadits E, Sperlágh B, Baranyi M, Csiba L, Hortobágyi T, Maglóczky Z, Martinecz B, Szabó G, Erdélyi F, Szipőcs R, Tamkun MM, Gesierich B, Duering M, Katona I, Liesz A, Tamás G, Dénes Á | title = Microglia monitor and protect neuronal function through specialized somatic purinergic junctions | journal = Science | volume = 367 | issue = 6477 | pages = 528–537 | date = January 2020 | pmid = 31831638 | doi = 10.1126/science.aax6752 | bibcode = 2020Sci...367..528C | url = https://epub.ub.uni-muenchen.de/76442/1/Cserep_Posfai_et_al_accepted.pdf }}</ref>

== <span class="anchor" id="origin_and_evolution_anchor">Origin and evolution</span>==
{{Main|Symbiogenesis}}

There are two hypotheses about the origin of mitochondria: [[endosymbiotic theory|endosymbiotic]] and [[autotransplantation|autogenous]]. The endosymbiotic hypothesis suggests that mitochondria were originally [[Prokaryote|prokaryotic]] cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became [[endosymbiont]]s living inside the eukaryote.<ref name="Gabaldón-2021"/><ref name="McCutcheon-2021">{{cite journal | vauthors = McCutcheon JP | title = The Genomics and Cell Biology of Host-Beneficial Intracellular Infections | journal = Annual Review of Cell and Developmental Biology | volume = 37 | issue = 1 | pages = 115–142 | date = October 2021 | pmid = 34242059 | doi = 10.1146/annurev-cellbio-120219-024122 | doi-access = free }}</ref><ref name="Callier-2022">{{cite journal |last1=Callier |first1=Viviane |title=Mitochondria and the origin of eukaryotes |journal=Knowable Magazine |date=8 June 2022 |doi=10.1146/knowable-060822-2 |doi-access=free }}</ref><ref name="Margulis-1986">{{cite book | vauthors = Margulis L, Sagan D |year= 1986 |title= Origins of Sex: Three billion years of genetic recombination |location= New Haven, CT |publisher= Yale University Press |pages= [https://archive.org/details/originsofsexthre00marg/page/69 69–71, 87] |isbn= 978-0-300-03340-3 |url= https://archive.org/details/originsofsexthre00marg/page/69 }}</ref> In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with [[bacteria]], the endosymbiotic hypothesis is the more widely accepted of the two accounts.<ref name="Margulis-1986"/><ref>{{cite book | vauthors = Martin WF, Müller M | year = 2007 | title = Origin of mitochondria and hydrogenosomes | publisher = Springer Verlag | location = Heidelberg, DE }}</ref>

A [[Mitochondrial DNA|mitochondrion contains DNA]], which is organized as several copies of a single, usually [[Mitochondrial DNA#Circular versus linear|circular]] [[chromosome]]. This mitochondrial chromosome contains genes for [[redox]] proteins, such as those of the respiratory chain. The [[CoRR hypothesis]] proposes that this co-location is required for redox regulation. The mitochondrial [[genome]] codes for some [[RNA]]s of [[ribosome]]s, and the 22&nbsp;[[tRNA]]s necessary for the translation of [[mRNA]]s into protein. The circular structure is also found in prokaryotes. The [[proto-mitochondrion]] was probably closely related to the order ''[[Rickettsiales]]'', which is in class Alphaproteobactera of phylum Pseudomonadota.<ref>{{cite journal | vauthors = Emelyanov VV | title = Mitochondrial connection to the origin of the eukaryotic cell | journal = European Journal of Biochemistry | volume = 270 | issue = 8 | pages = 1599–1618 | date = April 2003 | pmid = 12694174 | doi = 10.1046/j.1432-1033.2003.03499.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Müller M, Martin W | title = The genome of Rickettsia prowazekii and some thoughts on the origin of mitochondria and hydrogenosomes | journal = BioEssays | volume = 21 | issue = 5 | pages = 377–381 | date = May 1999 | pmid = 10376009 | doi = 10.1002/(sici)1521-1878(199905)21:5<377::aid-bies4>3.0.co;2-w }}</ref> However, the exact relationship of the ancestor of mitochondria to the [[alphaproteobacteria]] and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial.<ref>{{cite journal | vauthors = Gray MW, Burger G, Lang BF | title = Mitochondrial evolution | journal = Science | volume = 283 | issue = 5407 | pages = 1476–1481 | date = March 1999 | pmid = 10066161 | pmc = 3428767 | doi = 10.1126/science.283.5407.1476 | bibcode = 1999Sci...283.1476G }}</ref> For example, it has been suggested that the [[SAR11 clade]] of bacteria shares a relatively recent common ancestor with the mitochondria,<ref>{{cite journal | vauthors = Thrash JC, Boyd A, Huggett MJ, Grote J, Carini P, Yoder RJ, Robbertse B, Spatafora JW, Rappé MS, Giovannoni SJ | title = Phylogenomic evidence for a common ancestor of mitochondria and the SAR11 clade | journal = Scientific Reports | volume = 1 | issue = 1 | article-number = 13 | date = June 14, 2011 | pmid = 22355532 | pmc = 3216501 | doi = 10.1038/srep00013 | bibcode = 2011NatSR...1...13T }}</ref> while [[phylogenomic]] analyses indicate that mitochondria evolved from a [[Pseudomonadota]] lineage that is closely related to or a member of [[alphaproteobacteria]].<ref name="Martijn-2018">{{cite journal | vauthors = Martijn J, Vosseberg J, Guy L, Offre P, Ettema TJ | title = Deep mitochondrial origin outside the sampled alphaproteobacteria | journal = Nature | volume = 557 | issue = 7703 | pages = 101–105 | date = May 2018 | pmid = 29695865 | doi = 10.1038/s41586-018-0059-5 | bibcode = 2018Natur.557..101M | doi-access = free | hdl = 1874/373336 }}</ref><ref>{{cite journal | vauthors = Fan L, Wu D, Goremykin V, Xiao J, Xu Y, Garg S, Zhang C, Martin WF, Zhu R | title = Phylogenetic analyses with systematic taxon sampling show that mitochondria branch within Alphaproteobacteria | journal = Nature Ecology & Evolution | volume = 4 | issue = 9 | pages = 1213–1219 | date = September 2020 | pmid = 32661403 | doi = 10.1038/s41559-020-1239-x | bibcode = 2020NatEE...4.1213F | biorxiv = 10.1101/715870 }}</ref> Some papers describe mitochondria as sister to the alphaproteobacteria, together forming the sister the marineproteo1 group, together forming the sister to [[Magnetococcidae]].<ref>{{cite journal | vauthors = Wang S, Luo H | title = Dating Alphaproteobacteria evolution with eukaryotic fossils | journal = Nature Communications | volume = 12 | issue = 1 | article-number = 3324 | date = June 2021 | pmid = 34083540 | pmc = 8175736 | doi = 10.1038/s41467-021-23645-4 | bibcode = 2021NatCo..12.3324W }}</ref><ref>{{cite journal |vauthors=Esposti MD, Geiger O, Sanchez-Flores A |date=May 16, 2022 |title=On the bacterial ancestry of mitochondria: New insights with triangulated approaches |journal=bioRxiv |article-number=2022.05.15.491939 |doi=10.1101/2022.05.15.491939 }}</ref><ref>{{cite journal | vauthors = Muñoz-Gómez SA, Susko E, Williamson K, Eme L, Slamovits CH, Moreira D, López-García P, Roger AJ | title = Site-and-branch-heterogeneous analyses of an expanded dataset favour mitochondria as sister to known Alphaproteobacteria | journal = Nature Ecology & Evolution | volume = 6 | issue = 3 | pages = 253–262 | date = March 2022 | pmid = 35027725 | doi = 10.1038/s41559-021-01638-2 | bibcode = 2022NatEE...6..253M }}</ref><ref>{{cite journal | vauthors = Schön ME, Martijn J, Vosseberg J, Köstlbacher S, Ettema TJ | title = The evolutionary origin of host association in the Rickettsiales | journal = Nature Microbiology | volume = 7 | issue = 8 | pages = 1189–1199 | date = August 2022 | pmid = 35798888 | pmc = 9352585 | doi = 10.1038/s41564-022-01169-x }}</ref>

{{Clade|{{Clade
|state1=double
|1='' ''
|label2=[[Alphaproteobacteria|Alphaproteobacteria s.l.]]
|2={{Clade
|1=[[Magnetococcales]]
|2={{clade
|1=[[MarineProteo1]]
|2={{clade
|1='''Mitochondria'''
|2=[[Alphaproteobacteria|Alphaproteobacteria s.s.]]
}}
}}
}}
}}|label1=[[Pseudomonadota]]|style=font-size:75%;line-height:75%}}

The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.<ref name="O'Brien-2003">{{cite journal | vauthors = O'Brien TW | title = Properties of human mitochondrial ribosomes | journal = IUBMB Life | volume = 55 | issue = 9 | pages = 505–513 | date = September 2003 | pmid = 14658756 | doi = 10.1080/15216540310001626610 }}</ref> They closely resemble the bacterial [[Ribosome#Structure|70S]] ribosome and not the [[Ribosome#Structure|80S]] [[cytoplasm]]ic ribosomes, which are coded for by [[Cell nucleus|nuclear]] DNA.

The [[endosymbiotic]] relationship of mitochondria with their host cells was popularized by [[Lynn Margulis]].<ref>{{cite journal | vauthors = Sagan L | title = On the origin of mitosing cells | journal = Journal of Theoretical Biology | volume = 14 | issue = 3 | pages = 255–274 | date = March 1967 | pmid = 11541392 | doi = 10.1016/0022-5193(67)90079-3 | bibcode = 1967JThBi..14..225S }}</ref> The [[Symbiogenesis|endosymbiotic theory]] suggests that mitochondria descended from aerobic bacteria that somehow survived [[endocytosis]] by another cell, and became incorporated into the [[cytoplasm]]. The ability of these bacteria to conduct [[Cellular respiration|respiration]] in host cells that had relied on [[glycolysis]] and [[Fermentation (biochemistry)|fermentation]] would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7 to 2 billion years ago.<ref>{{cite journal | vauthors = Emelyanov VV | title = Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria | journal = Bioscience Reports | volume = 21 | issue = 1 | pages = 1–17 | date = February 2001 | pmid = 11508688 | doi = 10.1023/A:1010409415723 }}</ref><ref>{{cite journal | vauthors = Feng DF, Cho G, Doolittle RF | title = Determining divergence times with a protein clock: update and reevaluation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 24 | pages = 13028–13033 | date = November 1997 | pmid = 9371794 | pmc = 24257 | doi = 10.1073/pnas.94.24.13028 | doi-access = free | bibcode = 1997PNAS...9413028F }}</ref>
[[File:The-origins-of-mitochondrion-related-organelles-A-hypothetical-scenario-for-the.png|thumb|Evolution of mitochondrion related organelles (MROs)]]
A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: The [[microsporidia]]ns, [[metamonad]]s, and [[archamoebae]].<ref name="Cavalier-Smith-1991">{{cite journal | vauthors = Cavalier-Smith T | title = Archamoebae: the ancestral eukaryotes? | journal = Bio Systems | volume = 25 | issue = 1–2 | pages = 25–38 | year = 1991 | pmid = 1854912 | doi = 10.1016/0303-2647(91)90010-I | bibcode = 1991BiSys..25...25C }}</ref> These groups appear as the most primitive eukaryotes on [[phylogenetic trees]] constructed using [[rRNA]] information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of ''[[long-branch attraction]]'': They are derived groups and retain genes or organelles derived from mitochondria (e.&nbsp;g., [[mitosome]]s and [[hydrogenosome]]s).<ref name="Henze-2003"/> Hydrogenosomes, mitosomes, and related organelles as found in some [[loricifera]] (e.&nbsp;g. ''[[Spinoloricus]]'')<ref>{{cite journal | vauthors = Danovaro R, Dell'Anno A, Pusceddu A, Gambi C, Heiner I, Kristensen RM | title = The first metazoa living in permanently anoxic conditions | journal = BMC Biology | volume = 8 | article-number = 30 | date = April 2010 | pmid = 20370908 | pmc = 2907586 | doi = 10.1186/1741-7007-8-30 | doi-access = free }}</ref><ref>{{cite news |last1=Coghlan |first1=Andy |title=Zoologger: The mud creature that lives without oxygen |url=https://www.newscientist.com/article/dn18744-zoologger-the-mud-creature-that-lives-without-oxygen/ |work=New Scientist |date=7 April 2010 }}</ref> and [[myxozoa]] (e.&nbsp;g. ''[[Henneguya zschokkei]]'') are together classified as MROs, mitochondrion-related organelles.<ref name="Yahalomi-2020"/><ref name="Shiflett-2010">{{cite journal | vauthors = Shiflett AM, Johnson PJ | title = Mitochondrion-related organelles in eukaryotic protists | journal = Annual Review of Microbiology | volume = 64 | pages = 409–429 | year = 2010 | pmid = 20528687 | pmc = 3208401 | doi = 10.1146/annurev.micro.62.081307.162826 }}</ref>

''[[Monocercomonoides]]'' and other [[oxymonad]]s appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.<ref name="Karnkowska-2016"/><ref>{{cite journal |last1=Karnkowska |first1=Anna |last2=Treitli |first2=Sebastian C |last3=Brzoň |first3=Ondřej |last4=Novák |first4=Lukáš |last5=Vacek |first5=Vojtěch |last6=Soukal |first6=Petr |last7=Barlow |first7=Lael D |last8=Herman |first8=Emily K |last9=Pipaliya |first9=Shweta V |last10=Pánek |first10=Tomáš |last11=Žihala |first11=David |last12=Petrželková |first12=Romana |last13=Butenko |first13=Anzhelika |last14=Eme |first14=Laura |last15=Stairs |first15=Courtney W |last16=Roger |first16=Andrew J |last17=Eliáš |first17=Marek |last18=Dacks |first18=Joel B |last19=Hampl |first19=Vladimír |title=The Oxymonad Genome Displays Canonical Eukaryotic Complexity in the Absence of a Mitochondrion |journal=Molecular Biology and Evolution |date=1 October 2019 |volume=36 |issue=10 |pages=2292–2312 |doi=10.1093/molbev/msz147 |pmid=31387118 |pmc=6759080 }}</ref><ref name="Novák-2023">{{cite journal | vauthors = Novák LV, Treitli SC, Pyrih J, Hałakuc P, Pipaliya SV, Vacek V, Brzoň O, Soukal P, Eme L, Dacks JB, Karnkowska A, Eliáš M, Hampl V | title = Genomics of Preaxostyla Flagellates Illuminates the Path Towards the Loss of Mitochondria | journal = PLOS Genetics | volume = 19 | issue = 12 | article-number = e1011050 | date = December 2023 | pmid = 38060519 | pmc = 10703272 | doi = 10.1371/journal.pgen.1011050 | doi-access = free | veditors = Dutcher SK }}</ref>

==Mitochondrial genetics==
[[File:Map of the human mitochondrial genome.svg|thumb|right|300px|The [[Mitochondrial DNA#Circular versus linear|circular]] 16,569 bp human mitochondrial genome encoding 37 genes, ''i.e.'', 28 on the H-strand and 9 on the L-strand]]
{{Main|Mitochondrial DNA}}

Mitochondria contain their own genome. The [[Human mitochondrial genetics|human mitochondrial genome]] is a circular double-stranded [[DNA]] molecule of about 16&nbsp;[[base pair|kilobase]]s.<ref name="Chan-2006">{{cite journal | vauthors = Chan DC | title = Mitochondria: dynamic organelles in disease, aging, and development | journal = Cell | volume = 125 | issue = 7 | pages = 1241–1252 | date = June 2006 | pmid = 16814712 | doi = 10.1016/j.cell.2006.06.010 | doi-access = free }}</ref> It encodes 37 genes: 13 for [[Protein subunit|subunits]] of respiratory complexes I, III, IV and V, 22 for mitochondrial [[tRNA]] (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for [[rRNA]] (12S and 16S rRNA).<ref name="Chan-2006" /> One mitochondrion can contain two to ten copies of its DNA.<ref name="Wiesner-1992">{{cite journal | vauthors = Wiesner RJ, Rüegg JC, Morano I | title = Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues | journal = Biochemical and Biophysical Research Communications | volume = 183 | issue = 2 | pages = 553–559 | date = March 1992 | pmid = 1550563 | doi = 10.1016/0006-291X(92)90517-O }}</ref> One of the two mitochondrial DNA (mtDNA) strands has a disproportionately higher ratio of the heavier nucleotides adenine and guanine, and this is termed the heavy strand (or H strand), whereas the other strand is termed the light strand (or L strand). The weight difference allows the two strands to be separated by [[centrifugation]]. mtDNA has one long non-coding stretch known as the non-coding region (NCR), which contains the heavy strand promoter (HSP) and light strand promoter (LSP) for RNA transcription, the origin of replication for the H strand (OriH) localized on the L strand, three conserved sequence boxes (CSBs 1–3), and a termination-associated sequence (TAS). The origin of replication for the L strand (OriL) is localized on the H strand 11,000 bp downstream of OriH, located within a cluster of genes coding for tRNA.<ref>{{cite journal | vauthors = Falkenberg M | title = Mitochondrial DNA replication in mammalian cells: overview of the pathway | journal = Essays in Biochemistry | volume = 62 | issue = 3 | pages = 287–296 | date = July 2018 | pmid = 29880722 | pmc = 6056714 | doi = 10.1042/ebc20170100 }}</ref>

As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are [[transcription (genetics)|transcribed]] as multigenic transcripts, which are cleaved and [[Polyadenylation|polyadenylated]] to yield mature [[mRNA]]s. Most proteins necessary for mitochondrial function are encoded by genes in the [[cell nucleus]] and the corresponding proteins are imported into the mitochondrion.<ref name="Anderson-1981">{{cite journal | vauthors = Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG | title = Sequence and organization of the human mitochondrial genome | journal = Nature | volume = 290 | issue = 5806 | pages = 457–465 | date = April 1981 | pmid = 7219534 | doi = 10.1038/290457a0 | bibcode = 1981Natur.290..457A }}</ref> The exact number of genes encoded by the nucleus and the [[Mitochondrial DNA|mitochondrial genome]] differs between species. Most mitochondrial genomes are circular.<ref name="Fukuhara-1993">{{cite journal | vauthors = Fukuhara H, Sor F, Drissi R, Dinouël N, Miyakawa I, Rousset S, Viola AM | title = Linear mitochondrial DNAs of yeasts: frequency of occurrence and general features | journal = Molecular and Cellular Biology | volume = 13 | issue = 4 | pages = 2309–2314 | date = April 1993 | pmid = 8455612 | pmc = 359551 | doi = 10.1128/mcb.13.4.2309 }}</ref> In general, mitochondrial DNA lacks [[intron]]s, as is the case in the human mitochondrial genome;<ref name="Anderson-1981"/> however, introns have been observed in some eukaryotic mitochondrial DNA,<ref>{{cite journal | vauthors = Bernardi G | title = Intervening sequences in the mitochondrial genome | journal = Nature | volume = 276 | issue = 5688 | pages = 558–559 | date = December 1978 | pmid = 214710 | doi = 10.1038/276558a0 | bibcode = 1978Natur.276..558B }}</ref> such as that of [[yeast]]<ref>{{cite journal | vauthors = Hebbar SK, Belcher SM, Perlman PS | title = A maturase-encoding group IIA intron of yeast mitochondria self-splices in vitro | journal = Nucleic Acids Research | volume = 20 | issue = 7 | pages = 1747–1754 | date = April 1992 | pmid = 1579468 | pmc = 312266 | doi = 10.1093/nar/20.7.1747 }}</ref> and [[protist]]s,<ref>{{cite journal | vauthors = Gray MW, Lang BF, Cedergren R, Golding GB, Lemieux C, Sankoff D, Turmel M, Brossard N, Delage E, Littlejohn TG, Plante I, Rioux P, Saint-Louis D, Zhu Y, Burger G | title = Genome structure and gene content in protist mitochondrial DNAs | journal = Nucleic Acids Research | volume = 26 | issue = 4 | pages = 865–878 | date = February 1998 | pmid = 9461442 | pmc = 147373 | doi = 10.1093/nar/26.4.865 }}</ref> including ''[[Dictyostelium]] discoideum''.<ref>{{cite journal | vauthors = Gray MW, Lang BF, Burger G | title = Mitochondria of protists | journal = Annual Review of Genetics | volume = 38 | pages = 477–524 | year = 2004 | pmid = 15568984 | doi = 10.1146/annurev.genet.37.110801.142526 }}</ref> Between protein-coding regions, tRNAs are present. Mitochondrial tRNA genes have different sequences from the nuclear tRNAs, but lookalikes of mitochondrial tRNAs have been found in the nuclear chromosomes with high sequence similarity.<ref name="Telonis-2014">{{cite journal | vauthors = Telonis AG, Loher P, Kirino Y, Rigoutsos I | title = Nuclear and mitochondrial tRNA-lookalikes in the human genome | journal = Frontiers in Genetics | volume = 5 | page = 344 | year = 2014 | pmid = 25339973 | pmc = 4189335 | doi = 10.3389/fgene.2014.00344 | doi-access = free }}</ref>

In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the human body louse (''[[Pediculus humanus]]''). Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes.<ref name="Shao-2009">{{cite journal | vauthors = Shao R, Kirkness EF, Barker SC | title = The single mitochondrial chromosome typical of animals has evolved into 18 minichromosomes in the human body louse, Pediculus humanus | journal = Genome Research | volume = 19 | issue = 5 | pages = 904–912 | date = May 2009 | pmid = 19336451 | pmc = 2675979 | doi = 10.1101/gr.083188.108 }}</ref> This pattern is also found in other [[Anoplura|sucking lice]], but not in [[Mallophaga|chewing lice]]. Recombination has been shown to occur between the minichromosomes.

===Human population genetic studies===
{{Main|Human mitochondrial genetics}}

The near-absence of [[genetic recombination]] in mitochondrial DNA makes it a useful source of information for studying [[population genetics]] and [[evolutionary biology]].<ref>{{cite journal | vauthors = Castro JA, Picornell A, Ramon M | title = Mitochondrial DNA: a tool for populational genetics studies | journal = International Microbiology | volume = 1 | issue = 4 | pages = 327–332 | date = December 1998 | pmid = 10943382 }}</ref> Because all the mitochondrial DNA is inherited as a single unit, or [[haplotype]], the relationships between mitochondrial DNA from different individuals can be represented as a [[phylogenetic tree|gene tree]]. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in [[human evolutionary genetics]], where the [[molecular clock]] can be used to provide a recent date for [[mitochondrial Eve]].<ref>{{cite journal | vauthors = Cann RL, Stoneking M, Wilson AC | title = Mitochondrial DNA and human evolution | journal = Nature | volume = 325 | issue = 6099 | pages = 31–36 | date = January 1987 | pmid = 3025745 | doi = 10.1038/325031a0 | bibcode = 1987Natur.325...31C }}</ref><ref>{{cite journal | vauthors = Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ | title = Harvesting the fruit of the human mtDNA tree | journal = Trends in Genetics | volume = 22 | issue = 6 | pages = 339–345 | date = June 2006 | pmid = 16678300 | doi = 10.1016/j.tig.2006.04.001 }}</ref> This is often interpreted as strong support for a recent modern human expansion [[Recent single-origin hypothesis|out of Africa]].<ref name="Garrigan-2006">{{cite journal | vauthors = Garrigan D, Hammer MF | title = Reconstructing human origins in the genomic era | journal = Nature Reviews. Genetics | volume = 7 | issue = 9 | pages = 669–680 | date = September 2006 | pmid = 16921345 | doi = 10.1038/nrg1941 }}</ref> Another human example is the sequencing of mitochondrial DNA from [[Neanderthal]] bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for the lack of interbreeding between Neanderthals and modern humans.<ref>{{cite journal | vauthors = Krings M, Stone A, Schmitz RW, Krainitzki H, Stoneking M, Pääbo S | title = Neandertal DNA sequences and the origin of modern humans | journal = Cell | volume = 90 | issue = 1 | pages = 19–30 | date = July 1997 | pmid = 9230299 | doi = 10.1016/S0092-8674(00)80310-4 | hdl-access = free  | hdl = 11858/00-001M-0000-0025-0960-8 }}</ref>

However, mitochondrial DNA reflects only the history of the females in a population. This can be partially overcome by the use of paternal genetic sequences, such as the [[genetic recombination|non-recombining]] region of the [[Y-chromosome]].<ref name="Garrigan-2006"/>

Recent measurements of the [[molecular clock]] for mitochondrial DNA<ref>{{cite journal | vauthors = Soares P, Ermini L, Thomson N, Mormina M, Rito T, Röhl A, Salas A, Oppenheimer S, Macaulay V, Richards MB | title = Correcting for purifying selection: an improved human mitochondrial molecular clock | journal = American Journal of Human Genetics | volume = 84 | issue = 6 | pages = 740–759 | date = June 2009 | pmid = 19500773 | pmc = 2694979 | doi = 10.1016/j.ajhg.2009.05.001 }}</ref> reported a value of 1 mutation every 7884 years dating back to the most recent common ancestor of humans and apes, which is consistent with estimates of mutation rates of autosomal DNA (10{{sup|−8}} per base per generation).<ref name="Nachman-2000">{{cite journal | vauthors = Nachman MW, Crowell SL | title = Estimate of the mutation rate per nucleotide in humans | journal = Genetics | volume = 156 | issue = 1 | pages = 297–304 | date = September 2000 | pmid = 10978293 | pmc = 1461236 | doi = 10.1093/genetics/156.1.297 }}</ref>

=== Alternative genetic code ===
<div style="border: 1px solid grey; float:right; margin-right:0.6em; padding:0.5em">
{|class="wikitable"
|+Exceptions to the standard genetic code in mitochondria<ref name="Alberts-2005"/>
|-
!Organism!!Codon!!Standard!!Mitochondria
|-
|[[Mammal]]s
|AGA,&nbsp;AGG
|Arginine
|Stop&nbsp;codon
|-
|[[Invertebrate]]s
|AGA, AGG
|Arginine
|Serine
|-
|[[Fungus|Fungi]]
|CUA
|Leucine
|Threonine
|- valign="top"
|rowspan=2|All of the above
|AUA
|Isoleucine
|Methionine
|-
|UGA
|Stop codon
|Tryptophan
|}
</div>
While slight variations on the standard [[genetic code]] had been predicted earlier,<ref>{{cite journal |last1=Crick |first1=F.H.C. |last2=Orgel |first2=L.E. |title=Directed panspermia |journal=Icarus |date=July 1973 |volume=19 |issue=3 |pages=341–346 |doi=10.1016/0019-1035(73)90110-3 |bibcode=1973Icar...19..341C }}</ref> none was discovered until 1979, when researchers studying [[human mitochondrial genetics|human mitochondrial genes]] determined that they used an alternative code.<ref>{{cite journal | vauthors = Barrell BG, Bankier AT, Drouin J | title = A different genetic code in human mitochondria | journal = Nature | volume = 282 | issue = 5735 | pages = 189–194 | date = November 1979 | pmid = 226894 | doi = 10.1038/282189a0 | bibcode = 1979Natur.282..189B }}</ref> Nonetheless, the mitochondria of many other eukaryotes, including most plants, use the standard code.<ref name="Elzanowski-2019">{{Cite web|url=https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi|access-date=February 10, 2023|website=www.ncbi.nlm.nih.gov|title=The Genetic Codes|vauthors=Elzanowski A, Ostell J|date=January 7, 2019|archive-date=May 13, 2011|archive-url=https://web.archive.org/web/20110513014234/http://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi|url-status=live}}</ref> Many slight variants have been discovered since,<ref name="Elzanowski-2019"/> including various alternative mitochondrial codes.<ref>{{cite journal | vauthors = Jukes TH, Osawa S | title = The genetic code in mitochondria and chloroplasts | journal = Experientia | volume = 46 | issue = 11–12 | pages = 1117–1126 | date = December 1990 | pmid = 2253709 | doi = 10.1007/BF01936921 }}</ref> Further, the AUA, AUC, and AUU codons are all allowable start codons.

Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of [[RNA editing]], which is common in mitochondria. In higher plants, it was thought that CGG encoded for [[tryptophan]] and not [[arginine]]; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the standard [[genetic code]] for tryptophan.<ref>{{cite journal | vauthors = Hiesel R, Wissinger B, Schuster W, Brennicke A | title = RNA editing in plant mitochondria | journal = Science | volume = 246 | issue = 4937 | pages = 1632–1634 | date = December 1989 | pmid = 2480644 | doi = 10.1126/science.2480644 | bibcode = 1989Sci...246.1632H }}</ref> Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.<ref>{{cite journal | vauthors = Abascal F, Posada D, Knight RD, Zardoya R | title = Parallel evolution of the genetic code in arthropod mitochondrial genomes | journal = PLOS Biology | volume = 4 | issue = 5 | article-number = e127 | date = May 2006 | pmid = 16620150 | pmc = 1440934 | doi = 10.1371/journal.pbio.0040127 | doi-access = free }}</ref>

===Replication and inheritance===
{{Main|Mitochondrial fission}}
Mitochondria divide by [[mitochondrial fission]], a form of [[binary fission]] that is also done by bacteria<ref>{{cite book| vauthors = Pfeiffer RF |title=Parkinson's Disease|year=2012|publisher=CRC Press|page=583|url=https://books.google.com/books?id=uWI0Ia3mkf8C&pg=PA583 |isbn=978-1-4398-0714-9 }}</ref> although the process is tightly regulated by the host eukaryotic cell and involves communication between and contact with several other organelles. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division are linked to the [[cell cycle]]. For example, a single mitochondrion may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (in mammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When energy use is low, mitochondria are destroyed or become inactive. In such examples mitochondria are apparently randomly distributed to the daughter cells during the division of the [[cytoplasm]]. Mitochondrial dynamics, the balance between [[mitochondrial fusion]] and [[mitochondrial fission|fission]], is an important factor in pathologies associated with several disease conditions.<ref>{{cite journal | vauthors = Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C | title = New insights into the role of mitochondria in aging: mitochondrial dynamics and more | journal = Journal of Cell Science | volume = 123 | issue = Pt 15 | pages = 2533–2542 | date = August 2010 | pmid = 20940129 | pmc = 2912461 | doi = 10.1242/jcs.070490 }}</ref>

The hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional [[transmission electron microscopy]] (TEM). The resolution of fluorescence microscopy (≈200&nbsp;nm) is insufficient to distinguish structural details, such as double mitochondrial membrane in mitochondrial division or even to distinguish individual mitochondria when several are close together. Conventional TEM has also some technical limitations{{which|date=January 2016}} in verifying mitochondrial division. [[Cryo-electron tomography]] was recently used to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding.<ref>{{cite journal | vauthors = Hu GB | title = Whole cell cryo-electron tomography suggests mitochondria divide by budding | journal = Microscopy and Microanalysis | volume = 20 | issue = 4 | pages = 1180–1187 | date = August 2014 | pmid = 24870811 | doi = 10.1017/S1431927614001317 | bibcode = 2014MiMic..20.1180H }}</ref>

An individual's mitochondrial genes are inherited only from the mother, with rare exceptions.<ref name="McWilliams-2019">{{cite journal | vauthors = McWilliams TG, Suomalainen A | title = Mitochondrial DNA can be inherited from fathers, not just mothers | journal = Nature | volume = 565 | issue = 7739 | pages = 296–297 | date = January 2019 | pmid = 30643304 | doi = 10.1038/d41586-019-00093-1 | doi-access = free | bibcode = 2019Natur.565..296M }}</ref> In humans, when an [[ovum|egg cell]] is fertilized by a sperm, the mitochondria, and therefore the mitochondrial DNA, usually come from the egg only. The sperm's mitochondria enter the egg, but do not contribute genetic information to the embryo.<ref>Kimball, J.W. (2006) [http://home.comcast.net/~john.kimball1/BiologyPages/S/Sexual_Reproduction.html#Copulation_and_Fertilization "Sexual Reproduction in Humans: Copulation and Fertilization"] {{Webarchive|url=https://web.archive.org/web/20151002175927/http://home.comcast.net/~john.kimball1/BiologyPages/S/Sexual_Reproduction.html#Copulation_and_Fertilization |date=October 2, 2015 }}, ''Kimball's Biology Pages'' (based on ''Biology'', 6th ed., 1996)</ref> Instead, paternal mitochondria are marked with [[ubiquitin]] to select them for later destruction inside the [[embryo]].<ref>{{cite journal | vauthors = Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G | title = Ubiquitin tag for sperm mitochondria | journal = Nature | volume = 402 | issue = 6760 | pages = 371–372 | date = November 1999 | pmid = 10586873 | doi = 10.1038/46466 | bibcode = 1999Natur.402..371S }} Discussed in [http://www.sciencenews.org/20000101/fob3.asp ''Science News''] {{Webarchive|url=https://web.archive.org/web/20071219174548/http://www.sciencenews.org/20000101/fob3.asp |date=December 19, 2007 }}.</ref> The egg cell contains relatively few mitochondria, but these mitochondria divide to populate the cells of the adult organism. This mode is seen in most organisms, including the majority of animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain [[conifer]]ous plants, although not in [[pine tree]]s and [[taxus|yew]]s.<ref>{{cite journal |author=Mogensen HL|year=1996 |title=The Hows and Whys of Cytoplasmic Inheritance in Seed Plants |journal=American Journal of Botany |volume=83 |pages=383–404 |doi=10.2307/2446172 |issue=3 |jstor=2446172}}</ref> For [[Mytilidae|Mytilids]]<!--'Mytilidae mussels' just sounds wrong to me, unlike 'mussels of the family Mytilidae'. But, by analogy with members of canidae = canids etc., why not use 'Mytilids'?-->, paternal inheritance only occurs within males of the species.<ref>{{cite journal | vauthors = Zouros E | title = The exceptional mitochondrial DNA system of the mussel family Mytilidae | journal = Genes & Genetic Systems | volume = 75 | issue = 6 | pages = 313–318 | date = December 2000 | pmid = 11280005 | doi = 10.1266/ggs.75.313 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sutherland B, Stewart D, Kenchington ER, Zouros E | title = The fate of paternal mitochondrial DNA in developing female mussels, Mytilus edulis: implications for the mechanism of doubly uniparental inheritance of mitochondrial DNA | journal = Genetics | volume = 148 | issue = 1 | pages = 341–347 | date = January 1998 | pmid = 9475744 | pmc = 1459795 | doi = 10.1093/genetics/148.1.341 }}</ref><ref>[http://mbe.library.arizona.edu/data/1995/1205/3stew.pdf Male and Female Mitochondrial DNA Lineages in the Blue Mussel ''(Mytilus edulis)'' Species Group] {{Webarchive|url=https://web.archive.org/web/20130518011756/http://mbe.library.arizona.edu/data/1995/1205/3stew.pdf |date=May 18, 2013 }} by Donald T. Stewart, Carlos Saavedra, Rebecca R. Stanwood, Amy 0. Ball, and Eleftherios Zouros</ref> It has been suggested that it occurs at a very low level in humans.<ref>{{cite journal | vauthors = Johns DR | title = Paternal transmission of mitochondrial DNA is (fortunately) rare | journal = Annals of Neurology | volume = 54 | issue = 4 | pages = 422–424 | date = October 2003 | pmid = 14520651 | doi = 10.1002/ana.10771 }}</ref>

[[Uniparental inheritance]] leads to little opportunity for [[genetic recombination]] between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA.<ref name="Wiesner-1992"/> What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.<ref>{{cite journal | vauthors = Thyagarajan B, Padua RA, Campbell C | title = Mammalian mitochondria possess homologous DNA recombination activity | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27536–27543 | date = November 1996 | pmid = 8910339 | doi = 10.1074/jbc.271.44.27536 | doi-access = free }}</ref> Further, evidence suggests that animal mitochondria can undergo recombination.<ref>{{cite journal | vauthors = Lunt DH, Hyman BC | title = Animal mitochondrial DNA recombination | journal = Nature | volume = 387 | issue = 6630 | page = 247 | date = May 1997 | pmid = 9153388 | doi = 10.1038/387247a0 | doi-access = free | bibcode = 1997Natur.387..247L }}</ref> The data are more controversial in humans, although indirect evidence of recombination exists.<ref>{{cite journal | vauthors = Eyre-Walker A, Smith NH, Smith JM | title = How clonal are human mitochondria? | journal = Proceedings. Biological Sciences | volume = 266 | issue = 1418 | pages = 477–483 | date = March 1999 | pmid = 10189711 | pmc = 1689787 | doi = 10.1098/rspb.1999.0662 }}</ref><ref>{{cite journal | vauthors = Awadalla P, Eyre-Walker A, Smith JM | title = Linkage disequilibrium and recombination in hominid mitochondrial DNA | journal = Science | volume = 286 | issue = 5449 | pages = 2524–2525 | date = December 1999 | pmid = 10617471 | doi = 10.1126/science.286.5449.2524 }}</ref>

Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to [[Muller's ratchet]], the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the [[Heteroplasmy#Mitochondrial bottleneck|mtDNA bottleneck]]. The bottleneck exploits [[cellular noise|stochastic processes in the cell]] to increase the cell-to-cell variability in [[heteroplasmy|mutant load]] as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilization or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,<ref>{{cite journal | vauthors = Cree LM, Samuels DC, de Sousa Lopes SC, Rajasimha HK, Wonnapinij P, Mann JR, Dahl HH, Chinnery PF | title = A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes | journal = Nature Genetics | volume = 40 | issue = 2 | pages = 249–254 | date = February 2008 | pmid = 18223651 | doi = 10.1038/ng.2007.63 }}</ref><ref>{{cite journal | vauthors = Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H | title = The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells | journal = Nature Genetics | volume = 39 | issue = 3 | pages = 386–390 | date = March 2007 | pmid = 17293866 | doi = 10.1038/ng1970 }}</ref><ref>{{cite journal | vauthors = Wai T, Teoli D, Shoubridge EA | title = The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes | journal = Nature Genetics | volume = 40 | issue = 12 | pages = 1484–1488 | date = December 2008 | pmid = 19029901 | doi = 10.1038/ng.258 }}</ref> with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.<ref>{{cite journal | vauthors = Johnston IG, Burgstaller JP, Havlicek V, Kolbe T, Rülicke T, Brem G, Poulton J, Jones NS | title = Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism | journal = eLife | volume = 4 | article-number = e07464 | date = June 2015 | pmid = 26035426 | pmc = 4486817 | doi = 10.7554/eLife.07464 | arxiv = 1512.02988 | doi-access = free }}</ref>

===DNA repair===

Mitochondria can repair oxidative [[DNA damage (naturally occurring)|DNA damage]] by mechanisms analogous to those occurring in the [[cell nucleus]]. The proteins employed in [[mitochondrial DNA|mtDNA]] repair are encoded by nuclear [[gene]]s, and are translocated to the mitochondria. The [[DNA repair]] pathways in mammalian mitochondria include [[base excision repair]], double-strand break repair, direct reversal and [[DNA mismatch repair|mismatch repair]].<ref name="Gredilla-2012">{{cite journal | vauthors = Gredilla R, Garm C, Stevnsner T | title = Nuclear and mitochondrial DNA repair in selected eukaryotic aging model systems | journal = Oxidative Medicine and Cellular Longevity | volume = 2012 | article-number = 282438 | date = 2012 | pmid = 23050036 | pmc = 3462412 | doi = 10.1155/2012/282438 | doi-access = free }}</ref><ref name="Saki-2017">{{cite journal | vauthors = Saki M, Prakash A | title = DNA damage related crosstalk between the nucleus and mitochondria | journal = Free Radical Biology & Medicine | volume = 107 | pages = 216–227 | date = June 2017 | pmid = 27915046 | pmc = 5449269 | doi = 10.1016/j.freeradbiomed.2016.11.050 }}</ref> Alternatively, DNA damage may be bypassed, rather than repaired, by translesion synthesis.

Of the several DNA repair process in mitochondria, the base excision repair pathway has been most comprehensively studied.<ref name="Saki-2017" /> Base excision repair is carried out by a sequence of enzyme-catalyzed steps that include recognition and excision of a damaged DNA base, removal of the resulting abasic site, end processing, gap filling and ligation. A common damage in mtDNA that is repaired by base excision repair is [[8-oxoguanine]] produced by oxidation of [[guanine]].<ref name="Leon-2016">{{cite journal | vauthors = Leon J, Sakumi K, Castillo E, Sheng Z, Oka S, Nakabeppu Y | title = 8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions | journal = Scientific Reports | volume = 6 | article-number = 22086 | date = February 2016 | pmid = 26912170 | pmc = 4766534 | doi = 10.1038/srep22086 | bibcode = 2016NatSR...622086L }}</ref>

Double-strand breaks can be repaired by [[homologous recombination]]al repair in both mammalian mtDNA<ref name="Dahal-2018">{{cite journal | vauthors = Dahal S, Dubey S, Raghavan SC | title = Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria | journal = Cellular and Molecular Life Sciences | volume = 75 | issue = 9 | pages = 1641–1655 | date = May 2018 | pmid = 29116362 | pmc = 11105789 | doi = 10.1007/s00018-017-2702-y }}</ref> and plant mtDNA.<ref name="Odahara-2007">{{cite journal | vauthors = Odahara M, Inouye T, Fujita T, Hasebe M, Sekine Y | title = Involvement of mitochondrial-targeted RecA in the repair of mitochondrial DNA in the moss, Physcomitrella patens | journal = Genes & Genetic Systems | volume = 82 | issue = 1 | pages = 43–51 | date = February 2007 | pmid = 17396019 | doi = 10.1266/ggs.82.43 | doi-access = free }}</ref> Double-strand breaks in mtDNA can also be repaired by [[microhomology-mediated end joining]].<ref name="Tadi-2016">{{cite journal | vauthors = Tadi SK, Sebastian R, Dahal S, Babu RK, Choudhary B, Raghavan SC | title = Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions | journal = Molecular Biology of the Cell | volume = 27 | issue = 2 | pages = 223–235 | date = January 2016 | pmid = 26609070 | pmc = 4713127 | doi = 10.1091/mbc.E15-05-0260 }}</ref> Although there is evidence for the repair processes of direct reversal and mismatch repair in mtDNA, these processes are not well characterized.<ref name="Saki-2017" />

===Lack of mitochondrial DNA===
Some organisms have lost mitochondrial DNA altogether. In these cases, genes encoded by the mitochondrial DNA have been lost or transferred to the nucleus.<ref name="Chan-2006"/> ''[[Cryptosporidium]]'' have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.<ref name="Henriquez-2005">{{cite journal | vauthors = Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW | title = The unusual mitochondrial compartment of Cryptosporidium parvum | journal = Trends in Parasitology | volume = 21 | issue = 2 | pages = 68–74 | date = February 2005 | pmid = 15664529 | doi = 10.1016/j.pt.2004.11.010 }}</ref> In ''Cryptosporidium'', the mitochondria have an altered [[Adenosine triphosphate|ATP]] generation system that renders the parasite resistant to many classical mitochondrial [[enzyme inhibitor|inhibitors]] such as [[cyanide]], [[azide]], and [[atovaquone]].<ref name="Henriquez-2005"/> Mitochondria that lack their own DNA have been found in a marine parasitic [[dinoflagellate]] from the genus ''[[Amoebophrya]]''. This microorganism, ''A. cerati'', has functional mitochondria that lack a genome.<ref>{{cite journal | vauthors = John U, Lu Y, Wohlrab S, Groth M, Janouškovec J, Kohli GS, Mark FC, Bickmeyer U, Farhat S, Felder M, Frickenhaus S, Guillou L, Keeling PJ, Moustafa A, Porcel BM, Valentin K, Glöckner G | title = An aerobic eukaryotic parasite with functional mitochondria that likely lacks a mitochondrial genome | journal = Science Advances | volume = 5 | issue = 4 | article-number = eaav1110 | date = April 2019 | pmid = 31032404 | pmc = 6482013 | doi = 10.1126/sciadv.aav1110 | bibcode = 2019SciA....5.1110J }}</ref> In related species, the mitochondrial genome still has three genes, but in ''A. cerati'' only a single mitochondrial gene — the [[Cytochrome c oxidase subunit I|cytochrome c oxidase I]] gene (''cox1'') — is found, and it has migrated to the genome of the nucleus.<ref>{{Cite web|url=https://www.sciencedaily.com/releases/2019/04/190424153617.htm|title=Veritable powerhouse{{snd}}even without DNA: Parasitic algae from the dinoflagellate lineage have organized their genetic material in an unprecedented way|website=ScienceDaily|access-date=May 8, 2019|archive-date=June 24, 2019|archive-url=https://web.archive.org/web/20190624001930/https://www.sciencedaily.com/releases/2019/04/190424153617.htm|url-status=live}}</ref>

==Dysfunction and disease==

===Mitochondrial diseases===
{{Main|Mitochondrial disease}}

Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present as neurological disorders, including [[autism]].<ref name="Griffiths-2017" /> They can also manifest as [[myopathy]], [[diabetes]], multiple [[endocrinopathy]], and a variety of other systemic disorders.<ref name="Zeviani-2004">{{cite journal | vauthors = Zeviani M, Di Donato S | title = Mitochondrial disorders | journal = Brain | volume = 127 | issue = Pt 10 | pages = 2153–2172 | date = October 2004 | pmid = 15358637 | doi = 10.1093/brain/awh259 | doi-access = free }}</ref> Diseases caused by mutation in the mtDNA include [[Kearns–Sayre syndrome]], [[MELAS syndrome]] and [[Leber's hereditary optic neuropathy]].<ref name="Taylor-2005">{{cite journal | vauthors = Taylor RW, Turnbull DM | title = Mitochondrial DNA mutations in human disease | journal = Nature Reviews. Genetics | volume = 6 | issue = 5 | pages = 389–402 | date = May 2005 | pmid = 15861210 | pmc = 1762815 | doi = 10.1038/nrg1606 }}</ref> In the vast majority of cases, these diseases are transmitted by a female to her children, as the [[zygote]] derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, [[Pearson syndrome]], and progressive external [[ophthalmoparesis|ophthalmoplegia]] are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, [[MERRF syndrome]], and others are due to [[point mutation]]s in mtDNA.<ref name="Zeviani-2004" />

It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria which suggested an increase in mitochondrial biogenesis.<ref name="Goldman-2019">{{cite journal | vauthors = Goldman A, Khiste S, Freinkman E, Dhawan A, Majumder B, Mondal J, Pinkerton AB, Eton E, Medhi R, Chandrasekar V, Rahman MM, Ichimura T, Gopinath KS, Majumder P, Kohandel M, Sengupta S | title = Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance | journal = Science Signaling | volume = 12 | issue = 595 | date = August 2019 | pmid = 31431543 | pmc = 7261372 | doi = 10.1126/scisignal.aas8779 }}</ref> A 2022 study in ''Nature Nanotechnology'' has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.<ref>{{cite journal | vauthors = Saha T, Dash C, Jayabalan R, Khiste S, Kulkarni A, Kurmi K, Mondal J, Majumder PK, Bardia A, Jang HL, Sengupta S | title = Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells | journal = Nature Nanotechnology | volume = 17 | issue = 1 | pages = 98–106 | date = January 2022 | pmid = 34795441 | pmc = 10071558 | doi = 10.1038/s41565-021-01000-4 | bibcode = 2022NatNa..17...98S }}</ref>

In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in [[Friedreich's ataxia]], [[hereditary spastic paraplegia]], and [[Wilson's disease]].<ref>{{cite journal | vauthors = Chinnery PF, Schon EA | title = Mitochondria | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 74 | issue = 9 | pages = 1188–1199 | date = September 2003 | pmid = 12933917 | pmc = 1738655 | doi = 10.1136/jnnp.74.9.1188 }}</ref> These diseases are inherited in a [[dominance relationship]], as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as [[coenzyme Q10]] deficiency and [[Barth syndrome]].<ref name="Zeviani-2004"/> Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between [[pesticide]] exposure and the later onset of [[Parkinson's disease]].<ref>{{cite journal | vauthors = Sherer TB, Betarbet R, Greenamyre JT | title = Environment, mitochondria, and Parkinson's disease | journal = The Neuroscientist | volume = 8 | issue = 3 | pages = 192–197 | date = June 2002 | pmid = 12061498 | doi = 10.1177/1073858402008003004 }}</ref><ref>{{cite journal | vauthors = Gomez C, Bandez MJ, Navarro A | title = Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome | journal = Frontiers in Bioscience | volume = 12 | pages = 1079–1093 | date = January 2007 | pmid = 17127363 | doi = 10.2741/2128 | doi-access = free }}</ref> Other pathologies with etiology involving mitochondrial dysfunction include [[schizophrenia]], [[bipolar disorder]], [[dementia]], [[Alzheimer's disease]],<ref>{{cite journal | vauthors = Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, Guilhaus M, Ittner LM, Eckert A, Götz J | title = Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction | journal = Proteomics | volume = 10 | issue = 8 | pages = 1621–1633 | date = April 2010 | pmid = 20186753 | doi = 10.1002/pmic.200900651 }}</ref><ref>{{cite journal | vauthors = King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ | title = Molecular basis of substrate recognition and degradation by human presequence protease | journal = Structure | volume = 22 | issue = 7 | pages = 996–1007 | date = July 2014 | pmid = 24931469 | pmc = 4128088 | doi = 10.1016/j.str.2014.05.003 }}</ref> Parkinson's disease, [[epilepsy]], [[stroke]], [[cardiovascular disease]], [[myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS), [[retinitis pigmentosa]], and [[diabetes mellitus]].<ref>{{cite journal | vauthors = Schapira AH | title = Mitochondrial disease | journal = Lancet | volume = 368 | issue = 9529 | pages = 70–82 | date = July 2006 | pmid = 16815381 | doi = 10.1016/S0140-6736(06)68970-8 }}</ref><ref name="Pieczenik-2007">{{cite journal | vauthors = Pieczenik SR, Neustadt J | title = Mitochondrial dysfunction and molecular pathways of disease | journal = Experimental and Molecular Pathology | volume = 83 | issue = 1 | pages = 84–92 | date = August 2007 | pmid = 17239370 | doi = 10.1016/j.yexmp.2006.09.008 }}</ref>

Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in [[type 2 diabetics]]. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases [[uncoupling proteins]] (UCPs) and potentiate proton leakage through the [[adenine nucleotide translocator]] (ANT), the combination of which [[uncoupler|uncouples]] the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria are uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. Decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.<ref>{{cite journal | vauthors = Bugger H, Abel ED | title = Mitochondria in the diabetic heart | journal = Cardiovascular Research | volume = 88 | issue = 2 | pages = 229–240 | date = November 2010 | pmid = 20639213 | pmc = 2952534 | doi = 10.1093/cvr/cvq239 }}</ref>

Mitochondria also modulate processes such as testicular somatic cell development, spermatogonial stem cell differentiation, luminal acidification, testosterone production in testes, and more. Thus, dysfunction of mitochondria in spermatozoa can be a cause for infertility.<ref>{{cite journal | vauthors = Podolak A, Woclawek-Potocka I, Lukaszuk K | title = The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA? | journal = Cells | volume = 11 | issue = 5 | page = 797 | date = February 2022 | pmid = 35269419 | pmc = 8909547 | doi = 10.3390/cells11050797 | doi-access = free }}</ref>

In efforts to combat mitochondrial disease, [[mitochondrial replacement therapy]] (MRT) has been developed. This form of in vitro fertilization uses donor mitochondria, which avoids the transmission of diseases caused by mutations of mitochondrial DNA.<ref>{{cite journal | vauthors = May-Panloup P, Boguenet M, Hachem HE, Bouet PE, Reynier P | title = Embryo and Its Mitochondria | journal = Antioxidants | volume = 10 | issue = 2 | page = 139 | date = January 2021 | pmid = 33498182 | pmc = 7908991 | doi = 10.3390/antiox10020139 | doi-access = free }}</ref> However, this therapy is still being researched and can introduce genetic modification, as well as safety concerns. These diseases are rare but can be extremely debilitating and progressive diseases, thus posing complex ethical questions for public policy.<ref>{{Citation | veditors = Claiborne A, English R, Kahn J |title=Introduction |date=March 17, 2016 |url=https://www.ncbi.nlm.nih.gov/books/NBK355458/ |work=Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations |access-date=December 5, 2023 |publisher=National Academies Press (US) |language=en|vauthors=((Committee on the Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases; Board on Health Sciences Policy; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine))}}</ref>

===Relationships to aging===
{{See also|Hallmarks of aging#Mitochondrial dysfunction}}

There may be some leakage of the [[Electron transport chain|electrons transferred]] in the respiratory chain to form [[reactive oxygen species]]. This was thought to result in significant [[oxidative stress]] in the mitochondria with high mutation rates of mitochondrial DNA.<ref>{{cite journal | vauthors = Richter C, Park JW, Ames BN | title = Normal oxidative damage to mitochondrial and nuclear DNA is extensive | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 17 | pages = 6465–6467 | date = September 1988 | pmid = 3413108 | pmc = 281993 | doi = 10.1073/pnas.85.17.6465 | doi-access = free | bibcode = 1988PNAS...85.6465R }}</ref> Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,<ref>{{cite journal | vauthors = Harman D | title = Aging: a theory based on free radical and radiation chemistry | journal = Journal of Gerontology | volume = 11 | issue = 3 | pages = 298–300 | date = July 1956 | pmid = 13332224 | doi = 10.1093/geronj/11.3.298 | citeseerx = 10.1.1.663.3809 }}</ref> which was later refined into the [[Mitochondrial theory of ageing|mitochondrial free radical theory of aging]].<ref>{{cite journal | vauthors = Harman D | title = The biologic clock: the mitochondria? | journal = Journal of the American Geriatrics Society | volume = 20 | issue = 4 | pages = 145–147 | date = April 1972 | pmid = 5016631 | doi = 10.1111/j.1532-5415.1972.tb00787.x }}</ref> A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress.

A number of changes can occur to mitochondria during the aging process.<ref>{{cite web |url= http://www.circuitblue.com/biogerontology/mito.shtml |title= Mitochondria and Aging |publisher= circuitblue.co |access-date= October 23, 2006 |archive-date= September 29, 2017 |archive-url= https://web.archive.org/web/20170929210338/http://circuitblue.com/biogerontology/mito.shtml |url-status= live }}</ref> Tissues from elderly humans show a decrease in enzymatic activity of the proteins of the respiratory chain.<ref>{{cite journal | vauthors = Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S | title = Decline with age of the respiratory chain activity in human skeletal muscle | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1226 | issue = 1 | pages = 73–82 | date = April 1994 | pmid = 8155742 | doi = 10.1016/0925-4439(94)90061-2 }}</ref> However, mutated mtDNA can only be found in about 0.2% of very old cells.<ref>{{cite journal | vauthors = de Grey AD | title = Mitochondrial mutations in mammalian aging: an over-hasty about-turn? | journal = Rejuvenation Research | volume = 7 | issue = 3 | pages = 171–174 | year = 2004 | pmid = 15588517 | doi = 10.1089/rej.2004.7.171 }}</ref> Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of [[oxidative stress]] and neuronal death in [[Parkinson's disease]].<ref>{{cite journal | vauthors = Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM | title = High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 515–517 | date = May 2006 | pmid = 16604074 | doi = 10.1038/ng1769 }}</ref> Mitochondrial dysfunction has also been shown to occur in [[amyotrophic lateral sclerosis]].<ref>{{cite journal | vauthors = Mehta AR, Walters R, Waldron FM, Pal S, Selvaraj BT, Macleod MR, Hardingham GE, Chandran S, Gregory JM | title = Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: a systematic review and meta-analysis | journal = Brain Communications | volume = 1 | issue = 1 | article-number = fcz009 | date = August 2019 | pmid = 32133457 | pmc = 7056361 | doi = 10.1093/braincomms/fcz009 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mehta AR, Gregory JM, Dando O, Carter RN, Burr K, Nanda J, Story D, McDade K, Smith C, Morton NM, Mahad DJ, Hardingham GE, Chandran S, Selvaraj BT | title = Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis | journal = Acta Neuropathologica | volume = 141 | issue = 2 | pages = 257–279 | date = February 2021 | pmid = 33398403 | pmc = 7847443 | doi = 10.1007/s00401-020-02252-5 | doi-access = free }}</ref>

Since mitochondria cover a pivotal role in the ovarian function, by providing ATP necessary for the development from germinal vesicle to mature [[oocyte]], a decreased mitochondria function can lead to inflammation, resulting in premature ovarian failure and accelerated ovarian aging. The resulting dysfunction is then reflected in quantitative (such as mtDNA copy number and mtDNA deletions), qualitative (such as mutations and strand breaks) and oxidative damage (such as dysfunctional mitochondria due to ROS), which are not only relevant in ovarian aging, but perturb oocyte-cumulus crosstalk in the ovary, are linked to genetic disorders (such as Fragile X) and can interfere with embryo selection.<ref>{{cite journal | vauthors = Chiang JL, Shukla P, Pagidas K, Ahmed NS, Karri S, Gunn DD, Hurd WW, Singh KK | title = Mitochondria in Ovarian Aging and Reproductive Longevity | journal = Ageing Research Reviews | volume = 63 | article-number = 101168 | date = November 2020 | pmid = 32896666 | pmc = 9375691 | doi = 10.1016/j.arr.2020.101168 }}</ref>

==History==
The first observations of intracellular structures that probably represented mitochondria were published in 1857, by the physiologist [[Albert von Kölliker|Albert von Kolliker]].<ref>{{cite journal |vauthors=Kölliker A |title=Einige Bemerkungen über die Endigungen der Hautnerven und den Bau der Muskeln |journal=Zeitschrift für wissenschaftliche Zoologie |date=1857 |volume=8 |pages=311–325 |url=https://www.biodiversitylibrary.org/item/49190#page/319/mode/1up |trans-title=Some remarks about the terminations of the cutaneous nerves and the structure of muscles |language=German |access-date=June 22, 2023 |archive-date=June 22, 2023 |archive-url=https://web.archive.org/web/20230622033955/https://www.biodiversitylibrary.org/item/49190#page/319/mode/1up |url-status=live }}  On p. 316, Kölliker described mitochondria which he observed in fresh frog muscles:  ''" ... sehr blasse rundliche Körnchen, welche in langen linienförmigen Zügen [...] wenn man einmal auf dieselben aufmerksam geworden ist."''  ( ... [they are] very faint round granules, which are embedded in the [muscle's] contractile substance in long linear trains.  These granules are located in the whole thickness of the muscle fiber, on the surface as in the interior, and [they] are so numerous that they appear as a not unimportant element of the muscle fibers, once one has become alert to them.)  Kölliker said (p. 321) that he had found mitochondria in the muscles of other animals.  In Figure 3 of  [https://www.biodiversitylibrary.org/item/49190#page/564/mode/1up Table XIV], Kölliker depicted mitochondria in frog muscles.</ref><ref name="Ernster-1981">{{cite journal | vauthors = Ernster L, Schatz G | title = Mitochondria: a historical review | journal = The Journal of Cell Biology | volume = 91 | issue = 3 Pt 2 | pages = 227s–255s | date = December 1981 | pmid = 7033239 | pmc = 2112799 | doi = 10.1083/jcb.91.3.227s }}</ref> [[Richard Altmann]], in 1890, established them as cell organelles and called them "bioblasts".<ref name="Ernster-1981"/><ref>{{cite book |vauthors=Altmann R |title=Die Elementarorganismen und ihre Beziehungen zu den Zellen |trans-title=Elementary Organisms and Their Relations to Cells |date=1890 |publisher=Veit & Co. |location=Leipzig, Germany |page=125 |url=https://www.deutschestextarchiv.de/book/view/altmann_elementarorganismen_1890?p=141 |language=German |access-date=June 23, 2023 |archive-date=June 23, 2023 |archive-url=https://web.archive.org/web/20230623002552/https://www.deutschestextarchiv.de/book/view/altmann_elementarorganismen_1890?p=141 |url-status=live }}  From p. 125:  ''"Da auch sonst mancherlei Umstände dafür sprechen, dass Mikroorganismen und Granula einander gleichwerthig sind und Elementarorganismen vorstellen, welche sich überall finden, wo lebendige Kräfte ausgelöst werden, so wollen wir sie mit dem gemeinschaftlichen Namen der Bioblasten bezeichnen."'' (Since otherwise some circumstances indicate that microorganisms and granula are equivalent to each other and suggest elementary organisms, which are to be found wherever living forces are unleashed, we will designate them with the collective name of "bioblasts".)</ref> In 1898, Carl Benda coined the term "mitochondria" from the [[Greek language|Greek]] {{lang|el|μίτος}}, {{transliteration|el|mitos}}, "thread", and {{lang|el|χονδρίον}}, {{transliteration|el|chondrion}}, "granule".<ref name="OnlineEtymDict">{{cite encyclopedia|title=mitochondria|url=http://www.etymonline.com/index.php?term=mitochondria&allowed_in_frame=0|dictionary=[[Online Etymology Dictionary]]|access-date=May 23, 2013|archive-date=March 4, 2016|archive-url=https://web.archive.org/web/20160304105458/http://www.etymonline.com/index.php?term=mitochondria&allowed_in_frame=0|url-status=live}}</ref><ref name="Ernster-1981"/><ref>{{cite journal | vauthors = Benda C | date = 1898 | title = Ueber die Spermatogenese der Vertebraten und höherer Evertebraten. II. Theil: Die Histiogenese der Spermien. | trans-title = On spermatogenesis in vertebrates and higher invertebrates. Part II: The histogenesis of sperm. | journal = Archiv für Physiologie | volume = 1898 | pages = 393–398 | url = https://www.biodiversitylibrary.org/item/109725#page/403/mode/1up | language = de | access-date = January 14, 2018 | archive-date = February 24, 2019 | archive-url = https://web.archive.org/web/20190224231523/https://www.biodiversitylibrary.org/item/109725#page/403/mode/1up | url-status = live }}  From p. 397:  After Brenda states that ''" ... ich bereits in vielen Zellarten aller möglichen Thierclassen gefunden habe, ... "'' ( ... I have already found [them (mitochondria)] in many types of cells of all possible classes of animals, ... ), he suggests:  ''"Ich möchte vorläufig vorschlagen, ihnen als Mitochondria eine besondere Stellung vorzubehalten, die ich in weiteren Arbeiten begründen werde."''  (I would like to suggest provisionally reserving for them, as "mitochondria", a special status which I will justify in further work.)
* {{cite journal |vauthors=Benda C |title=Weitere Mitteilungen über die Mitochondria |journal=Archiv für Physiologie: Verhandlungen der Berliner Physiologischen Gesellschaft |date=1899 |volume=1899 |pages=376–383 |url=https://www.biodiversitylibrary.org/item/109704#page/388/mode/1up |trans-title=Further reports on mitochondria |language=German |access-date=June 23, 2023 |archive-date=June 23, 2023 |archive-url=https://web.archive.org/web/20230623035548/https://www.biodiversitylibrary.org/item/109704#page/388/mode/1up |url-status=live }}</ref> [[Leonor Michaelis]] discovered that [[Janus green]] can be used as a [[supravital stain]] for mitochondria in 1900.<ref>{{cite journal |vauthors=Michaelis L |title=Die vitale Farbung, eine Darstellungsmethode der Zellgranula |journal=Archiv für Mikroskopische Anatomie und Entwicklungsgeschichte |trans-journal=Archive for Microscopic Anatomy and Ontogenesis |date=1900 |volume=55 |pages=558–575 |doi=10.1007/BF02977747 }}</ref> In 1904, [[Friedrich Meves]] made the first recorded observation of mitochondria in plants in cells of the white waterlily, ''[[Nymphaea alba]],''<ref name="Ernster-1981"/><ref>Ernster's citation {{cite journal |vauthors=Meves F |date=May 1908 |title=Die Chondriosomen als Träger erblicher Anlagen. Cytologische Studien am Hühnerembryo |journal=Archiv für Mikroskopische Anatomie |volume=72 |issue=1 |pages=816–867 |doi=10.1007/BF02982402 }} is wrong, correct citation is {{cite journal | vauthors = Meves F |year= 1904 |title=Über das Vorkommen von Mitochondrien bezw. Chondromiten in Pflanzenzellen |journal=Ber. Dtsch. Bot. Ges. |volume=22 |pages=284–286|doi= 10.1111/j.1438-8677.1904.tb05237.x }}, cited in Meves' 1908 paper and in {{cite journal |vauthors=Schmidt EW |year=1913 |title=Pflanzliche Mitochondrien |journal=Progressus Rei Botanicae |volume=4 |pages=164–183 |url=https://archive.org/stream/progressusreibot04lots/progressusreibot04lots_djvu.txt |access-date=September 21, 2012 }}, with confirmation of Nymphaea alba<!-- I was unable to access the full article, so I cannot confirm if "Nymphea" is Nymphaea. --></ref> and in 1908, along with [[Claudius Regaud]], suggested that they contain proteins and lipids. Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations.<ref>{{cite journal |vauthors=Kingsbury BF |title=Cytoplasmic fixation |journal=The Anatomical Record |date=1912 |volume=6 |issue=2 |pages=39–52 |doi=10.1002/ar.1090060202 }} From p. 47: " ... the mitochondria are the structural expression thereof [i.e., of the chemical reducing processes in the cytoplasm], ... "</ref><ref name="Ernster-1981"/> In 1913, [[Otto Heinrich Warburg]] linked respiration to particles which he had obtained from extracts of guinea-pig liver and which he called "grana".<ref>{{cite journal |vauthors=Warburg O |title=Über sauerstoffatmende Körnchen aus Leberzellen und über Sauerstoffatmung in Berkefeld-Filtraten wässriger Leberextrake |journal=Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere (Pfluger's Archive for All Physiology of Humans and Animals) |date=1913 |volume=154 |pages=599–617 |url=https://www.biodiversitylibrary.org/item/108058#page/613/mode/1up |trans-title=On respiring granules from liver cells and on respiration in Berkefeld filtrates of aqueous liver extracts |language=German |access-date=June 23, 2023 |archive-date=June 23, 2023 |archive-url=https://web.archive.org/web/20230623190650/https://www.biodiversitylibrary.org/item/108058#page/613/mode/1up |url-status=live }}</ref> Warburg and [[Heinrich Otto Wieland]], who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925, when [[David Keilin]] discovered [[cytochromes]], that the [[respiratory chain]] was described.<ref name="Ernster-1981"/>

In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one [[Oxygen|oxygen molecule]] can form four [[adenosine triphosphate]] (ATP) molecules, and in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by [[Fritz Albert Lipmann]]. In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known.<ref name="Ernster-1981"/> The introduction of [[Cell fractionation|tissue fractionation]] by [[Albert Claude]] allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. In 1946, he concluded that [[cytochrome oxidase]] and other enzymes responsible for the respiratory chain were isolated to the mitochondria. [[Eugene P. Kennedy|Eugene Kennedy]] and [[Albert L. Lehninger|Albert Lehninger]] discovered in 1948 that mitochondria are the site of [[oxidative phosphorylation]] in eukaryotes. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of [[Cellular respiration|cell respiration]] were determined to occur in the mitochondria.<ref name="Ernster-1981"/>

The first high-resolution electron [[micrographs]] appeared in 1952, replacing the Janus Green stains as the preferred way to visualize mitochondria.<ref name="Ernster-1981"/> This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell.

The popular term "powerhouse of the cell" was coined by [[Philip Siekevitz]] in 1957.<ref name="Siekevitz-1957">{{cite magazine |vauthors=Siekevitz P |title=Powerhouse of the cell |magazine=[[Scientific American]] |year=1957 |volume=197 |pages=131–140|doi=10.1038/scientificamerican0757-131 |issue=1|bibcode=1957SciAm.197a.131S }}</ref><ref>{{cite journal | vauthors = Milane L, Trivedi M, Singh A, Talekar M, Amiji M | title = Mitochondrial biology, targets, and drug delivery | journal = Journal of Controlled Release | volume = 207 | pages = 40–58 | date = June 2015 | pmid = 25841699 | doi = 10.1016/j.jconrel.2015.03.036 }}</ref>

In 1967, it was discovered that mitochondria contained [[ribosomes]].<ref>{{cite journal | vauthors = Martin WF, Garg S, Zimorski V | title = Endosymbiotic theories for eukaryote origin | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 370 | issue = 1678 | article-number = 20140330 | date = September 2015 | pmid = 26323761 | pmc = 4571569 | doi = 10.1098/rstb.2014.0330 }}</ref> In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA completed in 1976.<ref name="Ernster-1981"/> In November 2024, Researchers from the United States have discovered that mitochondria divide into two distinct forms when cells are starved, this could help explain and describe how cancers thrive in hostile conditions.<ref>{{cite journal |last1=Thompson |first1=Benjamin |last2=Bates |first2=Emily |title=Surprise finding reveals mitochondrial 'energy factories' come in two different types |journal=Nature |date=6 November 2024 |doi=10.1038/d41586-024-03646-1 |pmid=39506172 }}</ref>

== See also ==
{{div col|colwidth=20em}}
* [[Anti-mitochondrial antibodies]]
* [[Respirometry#Mitochondrial metabolic rates|Mitochondrial metabolic rates]]
* [[Mitochondrial permeability transition pore]]
* [[Mitophagy]]
* [[Nebenkern]]
* [[Oncocyte]]
* [[Oncocytoma]]
* [[Paternal mtDNA transmission]]
* [[Plastid]]
* [[Submitochondrial particle]]
{{div col end}}

== References ==
{{Reflist|32em}}

'''General'''
* {{NCBI-scienceprimer}}

== External links ==
{{Commons}}
* {{cite book| vauthors = Lane N | title = The Vital Question: Energy, Evolution, and the Origins of Complex Life| date = 2016| publisher = WW Norton & Company | isbn= 978-0-393-35297-9}}
* [https://xvivo.com/examples/powering-the-cell-mitochondria-2/ Powering the Cell Mitochondria] {{Webarchive|url=https://web.archive.org/web/20220817083144/https://xvivo.com/examples/powering-the-cell-mitochondria-2/ |date=August 17, 2022 }} – XVIVO Scientific Animation
* [http://www.Mitodb.com Mitodb.com] {{Webarchive|url=https://web.archive.org/web/20130703105544/http://www.mitodb.com/ |date=July 3, 2013 }} – The mitochondrial disease database.
* [http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMitoE.html Mitochondria Atlas] {{Webarchive|url=https://web.archive.org/web/20120629101035/http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMitoE.html |date=June 29, 2012 }} at [[University of Mainz]]
* [https://web.archive.org/web/20080821114550/http://www.mitochondrial.net/ Mitochondria Research Portal] at mitochondrial.net
* [https://web.archive.org/web/20100125062948/http://www.cytochemistry.net/Cell-biology/mitoch1.htm Mitochondria: Architecture dictates function] at cytochemistry.net
* [https://web.archive.org/web/20090418174136/http://bama.ua.edu/~hsmithso/class/bsc_495/mito-plastids/mito_web.html Mitochondria links] at [[University of Alabama]]
* [http://www.mitophysiology.org/ MIP] {{Webarchive|url=http://arquivo.pt/wayback/20160523200848/http://www.mitophysiology.org/ |date=May 23, 2016 }} Mitochondrial Physiology Society
* [http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20inner%20membrane 3D structures of proteins from inner mitochondrial membrane] {{Webarchive|url=https://web.archive.org/web/20110913122941/http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20inner%20membrane |date=September 13, 2011 }} at [[University of Michigan]]
* [http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20outer%20membrane 3D structures of proteins associated with outer mitochondrial membrane] {{Webarchive|url=https://web.archive.org/web/20110913122952/http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20outer%20membrane |date=September 13, 2011 }} at [[University of Michigan]]
* [https://web.archive.org/web/20171201205358/http://www.mitoproteins.org/ Mitochondrial Protein Partnership] at [[University of Wisconsin]]
* [https://web.archive.org/web/20220617065151/https://mitominer.mrc-mbu.cam.ac.uk/ MitoMiner – A mitochondrial proteomics database] at [[MRC Mitochondrial Biology Unit]]
* [http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=mitochondrion&Submit=Go&event=display&start=1 Mitochondrion – Cell Centered Database] {{Webarchive|url=https://web.archive.org/web/20111007111911/http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=mitochondrion&Submit=Go&event=display&start=1 |date=October 7, 2011 }}
* [http://www.sci.sdsu.edu/TFrey/MitoMovie.htm Mitochondrion Reconstructed by Electron Tomography] {{Webarchive|url=https://web.archive.org/web/20121114105026/http://www.sci.sdsu.edu/TFrey/MitoMovie.htm |date=November 14, 2012 }} at [[San Diego State University]]
* [https://web.archive.org/web/20031211051649/http://www.wadsworth.org/databank/electron/cryomito_dis2.html Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography]

{{Authority control}}
{{Mitochondrial enzymes}}
{{Organelles}}
{{Organisms et al.}}
{{Self-replicating organic structures}}

[[Category:Cellular respiration]]
[[Category:Endosymbiotic events]]
[[Category:Mitochondria| ]]