Mitochondrial Uncoupling

Stable Identifier
Homo sapiens
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Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family, and have been implicated in a wide range of physiological and pathological conditions. Physiological conditions include thermogenesis, fatty acid metabolism and protection against free radicals and ageing; pathological conditions include involvement in obesity, diabetes and degenerative, neurological and immunological diseases.

The UCPs share general structural features with the other mitochondrial transport carriers. They have a tripartite structure, consisting of three homologous sequence repeats of approximately 100 residues. The carriers also have a signature motif, which is repeated in all members of the family and in all three repeats. The transmembrane arrangement of UCPs is 6 alpha-helix regions (2 regions per repeat) spanning the lipid bilayer with the amino and carboxyl termini facing the cytosolic side. 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, which are 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.

UCP2 and UCP3 have high amino acid sequence homology to UCP1 (59 and 57% amino-acid identity respectively). UCP2 has been identified in lung, spleen, pancreatic beta-cells and kidney, whereas UCP3 is found in brown adipose tissue and skeletal muscle. Homologs of UCP2 and UCP3 are found in marsupials, birds, fish and plants.

Despite a low level of sequence homology with UCP1-3, UCP4 and UCP5 share their functional properties (Hoang et al. 2012).

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). The modest depolarization brought about by UCP activation is thought to diminish superoxide generation without significantly compromising ATP production, creating a protective, negative-feedback system that complements enzymatic defences against reactive oxygen species.

There is some evidence that this mechanism is important in the etiology of Parkninson's Disease. Deletion of Park7 (DJ-1) decreased the abundance of Ucp5 and Ucp4 mRNA and compromised mitochondrial uncoupling in response to oxidant stress (Guzman et al. 2010). This may explain the unusual accumulation of mitochondrial DNA mutations with age in SNc dopaminergic neurons (Bender et al. 2006). These mutations, which are attributable to accumulated superoxide exposure, diminish mitochondrial competence and promote phenotypic decline, proteostatic impairments and death (Nicholls 2008).

A number of 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 as well. These are the "fatty acid cycling" model and the "proton buffering" model.

Studies of mouse models and of 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
15738989 The mitochondrial uncoupling-protein homologues

Krauss, S, Zhang, CY, Lowell, BB

Nat Rev Mol Cell Biol 2005
14715917 Brown adipose tissue: function and physiological significance

Cannon, B, Nedergaard, J

Physiol Rev 2004
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
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
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