Reactome | Mitochondrial Uncoupling

Mitochondrial Uncoupling

Stable Identifier

R-HSA-166187

DOI

10.3180/R-HSA-166187.6

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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The protonmotive force across the inner mitochondrial membrane built up by respiratory electron transport does not go entirely into ATP production. Transport proteins of the SLC25 type utilize the gradient to symport small molecules with protons into the matrix, simultaneously generating heat ("thermogenesis"). UCP1 and AAC1 have been shown to import protons exclusively and are responsible for most heat generated in brown fat and other tissue, respectively (reviewed in Bertholet & Kirichok, 2022).

Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family. The crystal structure of one member of the family, the adenine nucleotide translocase, is known, and UCPs can be successfully folded into this structure to indicate their probable 3D arrangement (Pebay-Peyroula et al. 2003, Kunji 2004, Esteves & Brand 2005).

The most studied member of the family, UCP1, catalyzes adaptive thermogenesis (i.e., heat generation) in mammalian brown adipose tissue. It does so by promoting a leak of protons through the mitochondrial inner membrane, which uncouples ATP production from substrate oxidation, leading to fast oxygen consumption and ultimately to heat production. The thermogenic activity of UCP1 in brown adipose tissue plays an important role when the organism needs extra heat, e.g., during cold weather conditions (for small rodents), the cold stress of birth, or arousal from hibernation. UCP1 homologs have been found in lower vertebrates such as fish, where their role is unclear (Cannon & Nedergaard 2004, Jastroch et al. 2005).

The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by physiological concentrations of purine nucleotides. This inhibition is overcome by fatty acids released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding. Other activators include superoxide, retinoic acid, the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) and reactive alkenals, such as hydroxynonenal.

There is strong evidence that the regulated uncoupling caused by these proteins attenuates mitochondrial reactive oxygen species production, protects against cellular damage, and (in beta-cells) diminishes insulin secretion. There are also untested suggestions that their transport of fatty acids may be physiologically important (Brand & Esteves 2005, Esteves & Brand 2005, Krauss et al. 2005).

Several models have been proposed for the molecular mechanism by which fatty acids lead to increased proton conductance by UCP1 in brown adipose tissue mitochondria and presumably by the other UCPs. We have depicted the most likely model, the "fatty acid cycling" model, in this pathway .

Studies of mouse models and cultured human cells have suggested that oleoyl-phenylalanine, synthesized by extracellular PM20D1, may play a role in uncoupling independent of the action of UCPs (Long et al., 2016). Its synthesis and hydrolysis are annotated here.

Literature References

PubMed ID	Title	Journal	Year
14715917	Brown adipose tissue: function and physiological significance Cannon, B, Nedergaard, J	Physiol Rev	2004
15738989	The mitochondrial uncoupling-protein homologues Krauss, S, Zhang, CY, Lowell, BB	Nat Rev Mol Cell Biol	2005
15886331	Uncoupling protein 1 in fish uncovers an ancient evolutionary history of mammalian nonshivering thermogenesis Jastroch, M, Wuertz, S, Kloas, W, Klingenspor, M	Physiol Genomics	2005
14603310	Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside Pebay-Peyroula, E, Dahout-Gonzalez, C, Kahn, R, Trezeguet, V, Lauquin, GJ, Brandolin, G	Nature	2003
34758268	Mitochondrial H⁺ Leak and Thermogenesis Bertholet, AM, Kirichok, Y	Annu Rev Physiol	2022
16005426	The reactions catalysed by the mitochondrial uncoupling proteins UCP2 and UCP3 Esteves, TC, Brand, MD	Biochim Biophys Acta	2005
15111103	The role and structure of mitochondrial carriers Kunji, ER	FEBS Lett	2004
27374330	The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria Long, JZ, Svensson, KJ, Bateman, LA, Lin, H, Kamenecka, T, Lokurkar, IA, Lou, J, Rao, RR, Chang, MR, Jedrychowski, MP, Paulo, JA, Gygi, SP, Griffin, PR, Nomura, DK, Spiegelman, BM	Cell	2016
16098826	Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3 Brand, MD, Esteves, TC	Cell Metab	2005