Thermogenin

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Template:Short description Template:Cs1 config Template:Infobox gene Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1)<ref name="entrez">Template:Cite web</ref> is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio. Recent findings indicate that the UCP1 protein plays a crucial role in thermogenesis by catalyzing the dissipative production of heat through protons derived from NADH and FADH2. These electron carriers are produced in the TCA cycle from the oxidation of acetyl-CoA, which comes from the breakdown of free fatty acids. Intriguingly, the acetyl-CoA products undergo a recycling process that facilitates their re-utilization, thereby sustaining the cycle known as the HEAT cycle.<ref name="Mirza_2021">Template:Cite journal</ref>

Structure

File:Structure of the human uncoupling protein.png
Structure of the human uncoupling protein

The atomic structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy.<ref name="Jones_2023">Template:Cite journal</ref> The structure has the typical fold of a member of the SLC25 family.<ref name="Ruprecht_2020">Template:Cite journal</ref><ref name="Kunji_2020">Template:Cite journal</ref> UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak.<ref name="Jones_2023" />

Mechanism

File:ThermogeneseAdipozyten-en.svg
Mechanism of thermogenin activation: In a last step thermogenin inhibition is released through the presence of free fatty acids. The cascade is initiated by binding of norepinephrine to the cells β3-adrenoceptors.

UCP1 belongs to the UCP family which are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix and hence dissipating the proton gradient. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, where it provides a mechanism for the enormous heat-generating capacity of the tissue.

UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides.<ref>Template:Cite journal</ref> Fatty acids are released by the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state.

File:The Alternating Access Model for UCP1 with H+ as a Substrate.jpg
The Alternating Access Model for UCP1 with H+ as a Substrate

UCP1 is very similar to the ATP/ADP Carrier protein, or Adenine Nucleotide Translocator (ANT).<ref name="Crichton_2017">Template:Cite journal</ref><ref>Template:Cite journal</ref> The proposed alternating access model for UCP1 is based on the similar ANT mechanism.<ref>Template:Cite journal</ref> The substrate comes in to the half open UCP1 protein from the cytoplasmic side of the membrane, the protein closes the cytoplasmic side so the substrate is enclosed in the protein, and then the matrix side of the protein opens, allowing the substrate to be released into the mitochondrial matrix. The opening and closing of the protein is accomplished by the tightening and loosening of salt bridges at the membrane surface of the protein. Substantiation for this modelling of UCP1 on ANT is found in the many conserved residues between the two proteins that are actively involved in the transportation of substrate across the membrane. Both proteins are integral membrane proteins, localized to the inner mitochondrial membrane, and they have a similar pattern of salt bridges, proline residues, and hydrophobic or aromatic amino acids that can close or open when in the cytoplasmic or matrix state.<ref name="Crichton_2017" />

HEAT cycle

The HEAT Cycle is a proposed metabolic pseudo-futile cycle that occurs in the mitochondria of brown adipose tissue (BAT) and is essential for non-shivering thermogenesis. In a recent study on differential temperature-based analysis of cytoplasmic mitochondria (CM) and lipid droplet-anchored mitochondria (LDAM),<ref>Template:Cite journal</ref> it was observed that LDAM generate heat through uncoupling proteins, while CM not only produce heat but also enhance the overall cellular metabolism of brown fat cells (BFCs). At lower temperatures or during cold acclimation, brown fat cells (BFCs) initiate thermogenesis at the indirect cost of ATP. Free fatty acids (FFAs) are moved from the cytoplasm to the mitochondria where they undergo β-oxidation, producing one NADH and one FADH per cycle. Instead of entering the TCA cycle, acetyl-CoA from β-oxidation combines with oxaloacetate to form citrate. This citrate returns to the cytoplasm, where it is converted back into oxaloacetate and acetyl-CoA. The cytosolic acetyl-CoA is then used for fatty acid synthesis, fueled by NADPH. The newly synthesized FFAs can be transported back to the mitochondria, creating a cyclical process known as the HEAT cycle,<ref name="Mirza_2021" /> which illustrates the interplay of fatty acid synthesis and breakdown. The glycerol-3-phosphate (G3P) shuttle has been shown to be active at lower temperatures; it transfers cytoplasmic NADH to the mitochondria in the form of FADH. The HEAT cycle provides a comprehensive overview of the bioenergetics of brown fat cells (BFCs), highlighting the intricate interconnections within metabolic processes. Proteomic analysis of two mitochondrial subpopulations (cytoplasmic mitochondria; CM, lipid droplet-anchored mitochondria; LDAM) of BATs revealed that (BFCs) exhibit heightened expression of key proteins involved in several metabolic pathways, including glycolysis, gluconeogenesis, glyceroneogenesis, the pentose phosphate pathway related to nucleotide metabolism, fatty acid β-oxidation, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, as well as the electron transport chain. Pyruvate, the end product of glycolysis, is transported into the mitochondria where it is converted to acetyl-CoA, linking glycolytic and mitochondrial metabolism. This acetyl-CoA—derived from either glycolytic or β-oxidative sources—then condenses with oxaloacetate to form citrate. Notably, the citrate is shuttled back to the cytoplasm, where it plays a crucial role in fatty acid synthesis. In summary, the HEAT cycle serves as a cyto-mitochondrial pathway that integrates the breakdown and synthesis of fatty acids, ultimately facilitating themogenesis.

The NADH donates its protons to complex I (C-I) of the electron transport chain (ETC). The protons from NADH then move to ubiquinone, then to complex III (C-III), and finally to complex IV (C-IV), resulting in the production of water and ATP. ATP is synthesized by ATP synthase at each step of proton movement. Meanwhile, FADH donates its protons directly to C-III through ubiquinone in the ETC, also contributing to ATP and water production. It is known that in isolated mitochondrial samples of the ETC, 2.5 ATP molecules are produced from NADH and 1.5 ATP molecules from FADH.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Uncoupling protein (UCP1) disrupts the electron transport chain (ETC) by uncoupling protons, diverting them towards heat production instead of ATP synthesis.

Evolution

UCP1 is expressed in brown adipose tissue, which is functionally found only in eutherians. The UCP1, or thermogenin, gene likely arose in an ancestor of modern vertebrates, but did not initially allow for our vertebrate ancestor to use non-shivering thermogenesis for warmth. It wasn't until heat generation was adaptively selected for in placental mammal descendants of this common ancestor that UCP1 evolved its current function in brown adipose tissue to provide additional warmth.<ref>Template:Cite journal</ref> While UCP1 plays a key thermogenic role in a wide range of placental mammals, particularly those with small body size and those that hibernate, the UCP1 gene has lost functionality in several large-bodied lineages (e.g. horses, elephants, sea cows, whales and hyraxes) and lineages with low metabolic rates (e.g. pangolins, armadillos, sloths and anteaters).<ref>Template:Cite journal</ref> Recent discoveries of non-heat-generating orthologues of UCP1 in fish and marsupials, other descendants of the ancestor of modern vertebrates, show that this gene was passed on to all modern vertebrates, but aside from placental mammals, none have heat producing capability.<ref>Template:Cite journal</ref> This further suggests that UCP1 had a different original purpose and in fact phylogenetic and sequence analyses indicate that UCP1 is likely a mutated form of a dicarboxylate carrier protein that adapted for thermogenesis in placental mammals.<ref>Template:Cite journal</ref>

History

Researchers in the 1960s investigating brown adipose tissue, found that in addition to producing more heat than typical of other tissues, brown adipose tissue seemed to short circuit, or uncouple, respiration coupling.<ref>Template:Cite journal</ref> Uncoupling protein 1 was discovered in 1976 by David G. Nicholls, Vibeke Bernson, and Gillian Heaton, and the discovery was published in 1978 and shown to be the protein responsible for this uncoupling effect.<ref name="Nicholls_1978">Template:Cite book</ref> UCP1 was later purified for the first time in 1980 and was first cloned in 1988.<ref name="Kozak_1988">Template:Cite journal</ref><ref name="Bouillaud_1988">Template:Cite journal</ref>

Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3, UCP4, and UCP5 (also known as BMCP1 or SLC25A14).

Clinical relevance

Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.<ref>Template:Cite journal</ref>

See also

References

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Further reading

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