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Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1)^[1] is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis.

Mechanism

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.

UCPs 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. 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. Fatty acids cause 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). At the termination of thermogenesis, the mitochondria oxidize away the residual fatty acids, UCP1 inactivates and the cell resumes its normal energy-conserving mode.

History

Uncoupling protein 1 was discovered in 1978^[2] and was first cloned in 1988.^[3]^[4]

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 BMCP1 (also known as UCP5).

References

^ "Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier)".
^ Nicholls DG, Bernson VS, Heaton GM (1978). "The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation". Experientia Suppl. 32: 89–93. doi:10.1007/978-3-0348-5559-4_9. PMID 348493.
^ Kozak LP, Britton JH, Kozak UC, Wells JM (1988). "The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains". J. Biol. Chem. 263 (25): 12274–7. PMID 3410843.
^ Bouillaud F, Raimbault S, Ricquier D (1988). "The gene for rat uncoupling protein: complete sequence, structure of primary transcript and evolutionary relationship between exons". Biochem. Biophys. Res. Commun. 157 (2): 783–92. doi:10.1016/S0006-291X(88)80318-8. PMID 3202878.

External links

Seaweed anti-obesity tablet hope (BBC - Thermogenin mentioned as part of process)
thermogenin at the US National Library of Medicine Medical Subject Headings (MeSH)

English Journal

Uncoupling and reactive oxygen species (ROS) - A double-edged sword for β-cell function? "Moderation in all things".

Collins S, Pi J, Yehuda-Shnaidman E.SourceDiabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, SBMRI-Lake Nona, 6400 Sanger Road, Orlando, FL 32827, USA. Electronic address: scollins@sanfordburnham.org.
Best practice & research. Clinical endocrinology & metabolism.Best Pract Res Clin Endocrinol Metab.2012 Dec;26(6):753-8. doi: 10.1016/j.beem.2012.08.002. Epub 2012 Sep 18.
The ability of the mitochondrion to (a) manage fuel import to oxidize for adenosine tri-phosphate (ATP) generation while (b) protecting itself and the cellular environment from electron leak, which can generate highly reactive oxygen species (ROS) is a delicate balancing act. ATP is the currency of
PMID 23168277

Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and the protective effect of dimethoxy curcumin.

Lu J, Duan W, Guo Y, Jiang H, Li Z, Huang J, Hong K, Li C.SourceDepartment of Neurology, The Second Hospital of Hebei Medical University, Hebei, China.
Brain research bulletin.Brain Res Bull.2012 Dec 1;89(5-6):185-90. doi: 10.1016/j.brainresbull.2012.09.005. Epub 2012 Sep 15.
TAR-DNA-binding protein of 43kDa (TDP-43) was recently found to be one of the major disease proteins in the pathological inclusions of amyotrophic lateral sclerosis (ALS). The effect of TDP-43 on mitochondrial function remains poorly understood. Here, we show that human TDP-43 caused mitochondrial m
PMID 22986236

Japanese Journal

The Function and Pathology of Brown Adipose Tissue in Animals and Humans

IATROPOULOS Michael,WILLIAMS Gary
Journal of toxicologic pathology 17(2), 147-153, 2004-06-30
… The mt response involves a membranous protein in the inner membrane, uncoupling protein (UCP1) or thermogenin. …
NAID 10025851997

母体糖尿病が胎児褐色脂肪組織熱産生に及ぼす影響とその機構について

田所直子
千葉医学雑誌 67(6), 293-303, 1991-12-01
… また胎児褐色脂肪組織ミトコンドリア機能として外膜酵素蛋白であるacyl CoA synthetase活性とmonoamine oxidase活性,内膜酵素蛋白であるcytocnrome c oxidase活性とthermogenin量を測定した。 … 同じく内膜に存在するthermogenin量は軽症群では0.83nmol/mg prot. …
NAID 110006183549

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Uncoupling protein 1 (mitochondrial, proton carrier)
Identifiers
Symbols	UCP1 ; SLC25A7; UCP
External IDs	OMIM: 113730 MGI: 98894 HomoloGene: 22524 GeneCards: UCP1 Gene
Gene ontology
Molecular function	• oxidative phosphorylation uncoupler activity;
Cellular component	• mitochondrion; • mitochondrial inner membrane; • integral to membrane;
Biological process	• regulation of transcription from RNA polymerase II promoter; • mitochondrial transport; • proton transport; • respiratory electron transport chain; • small molecule metabolic process; • brown fat cell differentiation;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

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英: [[]]
同: thermogenin
関: [[]]

同: thermogenin

[entrez-1] "Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier)".

[pmid348493-2] Nicholls DG, Bernson VS, Heaton GM (1978). "The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation". Experientia Suppl. 32: 89–93. doi:10.1007/978-3-0348-5559-4_9. PMID 348493.

[pmid3410843-3] Kozak LP, Britton JH, Kozak UC, Wells JM (1988). "The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains". J. Biol. Chem. 263 (25): 12274–7. PMID 3410843.

[pmid3202878-4] Bouillaud F, Raimbault S, Ricquier D (1988). "The gene for rat uncoupling protein: complete sequence, structure of primary transcript and evolutionary relationship between exons". Biochem. Biophys. Res. Commun. 157 (2): 783–92. doi:10.1016/S0006-291X(88)80318-8. PMID 3202878.

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thermogenin