Mitochondrial Uncoupling Proteins

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.<br><br>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 (<i>Pebay-Peyroula et al., 2003; Kunji, 2004; Esteves and Brand, 2005</i>).<br><br>The paradigm of this 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 and arousal from hibernation. UCP1 homologs have also been found in lower vertebrates such as fish, where their role is still unclear (<i>Cannon and Nedergaard, 2004; Jastroch et al., 2005</i>).<br><br>The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by purine nucleotides at physiological concentrations, and this inhibition is overcome by fatty acids, which are released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding.<br><br>In the late 1990’s, UCP2 and UCP3 were identified. These new UCPs have high amino acid sequence homology to UCP1 (59 and 57% amino-acid identity to UCP1, 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.<br><br>UCP2 and UCP3 only catalyze proton leak when activated. These proteins will transport protons and increase the net proton conductance of mitochondria in the presence of specific activators, in a way that is inhibited by purine nucleotides. 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. Activation might require fatty acids. UCP1 is also activated by these compounds.<br><br>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 (<i>Brand and Esteves, 2005; Esteves and Brand, 2005; Krauss et al., 2005</i>).<br><br>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. Authored: Brand, MD, Esteves, TC, Jassal, B, 2005-11-09 10:46:33

http://purl.obolibrary.org/obo/HINO_0014477

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 and Brand, 2005).

The paradigm of this 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 and arousal from hibernation. UCP1 homologs have also been found in lower vertebrates such as fish, where their role is still unclear (Cannon and Nedergaard, 2004; Jastroch et al., 2005).

The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by purine nucleotides at physiological concentrations, and this inhibition is overcome by fatty acids, which are released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding.

In the late 1990’s, UCP2 and UCP3 were identified. These new UCPs have high amino acid sequence homology to UCP1 (59 and 57% amino-acid identity to UCP1, 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.

UCP2 and UCP3 only catalyze proton leak when activated. These proteins will transport protons and increase the net proton conductance of mitochondria in the presence of specific activators, in a way that is inhibited by purine nucleotides. 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. Activation might require fatty acids. UCP1 is also activated by these compounds.

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 and Esteves, 2005; Esteves and Brand, 2005; Krauss et al., 2005).

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.

Authored: Brand, MD, Esteves, TC, Jassal, B, 2005-11-09 10:46:33

Pubmed15886331

Reactome, http://www.reactome.org

Pubmed15738989

Pubmed14603310

Pubmed16098826

Pubmed16005426

Pubmed14715917

Pubmed15111103

Mitochondrial Uncoupling Proteins

http://purl.obolibrary.org/obo/NCBITaxon_9606

HINO:0014477

Mitochondrial Uncoupling Proteins

GENE ONTOLOGYGO:0015992

Reactome Database ID Release 43166187

ReactomeREACT_6341

http://purl.obolibrary.org/obo/INO_0000021

http://purl.obolibrary.org/obo/HINO_0014486

http://purl.obolibrary.org/obo/HINO_0014478