Thermogenin

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Uncoupling protein 1 (mitochondrial, proton carrier)
Identifiers
SymbolsUCP1; SLC25A7; UCP
External IDsOMIM: 113730 MGI: 98894 HomoloGene: 22524 GeneCards: UCP1 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez735022227
EnsemblENSG00000109424ENSMUSG00000031710
UniProtP25874P12242
RefSeq (mRNA)NM_021833NM_009463
RefSeq (protein)NP_068605NP_033489
Location (UCSC)Chr 4:
141.48 – 141.49 Mb		Chr 8:
83.29 – 83.3 Mb
PubMed search
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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. Non-shivering thermogenesis is the primary means of heat generation in hibernating mammals and in human infants.

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

  1. ↑ "Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier)". 
  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. PMID 348493. 
  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. 
  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. 

Further reading

  • Ricquier D, Bouillaud F (2000). "The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP". Biochem. J. 345 (2): 161–79. doi:10.1042/0264-6021:3450161. PMC 1220743. PMID 10620491. 
  • Muzzin P (2002). "The uncoupling proteins". Ann. Endocrinol. (Paris) 63 (2 Pt 1): 106–10. PMID 11994670. 
  • Del Mar Gonzalez-Barroso M, Ricquier D, Cassard-Doulcier AM (2002). "The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research". Obesity reviews : an official journal of the International Association for the Study of Obesity 1 (2): 61–72. PMID 12119988. 
  • Cassard AM, Bouillaud F, Mattei MG et al. (1990). "Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4". J. Cell. Biochem. 43 (3): 255–64. doi:10.1002/jcb.240430306. PMID 2380264. 
  • Bouillaud F, Villarroya F, Hentz E et al. (1988). "Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe". Clin. Sci. 75 (1): 21–7. PMID 3165741. 
  • Oppert JM, Vohl MC, Chagnon M et al. (1994). "DNA polymorphism in the uncoupling protein (UCP) gene and human body fat". Int. J. Obes. Relat. Metab. Disord. 18 (8): 526–31. PMID 7951471. 
  • Clément K, Ruiz J, Cassard-Doulcier AM et al. (1997). "Additive effect of A-->G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta 3-adrenergic receptor gene on weight gain in morbid obesity". Int. J. Obes. Relat. Metab. Disord. 20 (12): 1062–6. PMID 8968850. 
  • Schleiff E, Shore GC, Goping IS (1997). "Human mitochondrial import receptor, Tom20p. Use of glutathione to reveal specific interactions between Tom20-glutathione S-transferase and mitochondrial precursor proteins". FEBS Lett. 404 (2–3): 314–8. doi:10.1016/S0014-5793(97)00145-2. PMID 9119086. 
  • Urhammer SA, Fridberg M, Sørensen TI et al. (1998). "Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity". J. Clin. Endocrinol. Metab. 82 (12): 4069–74. doi:10.1210/jc.82.12.4069. PMID 9398715. 
  • Jezek P, Urbánková E (2000). "Specific sequence of motifs of mitochondrial uncoupling proteins". IUBMB Life 49 (1): 63–70. doi:10.1080/713803586. PMID 10772343. 
  • Mori H, Okazawa H, Iwamoto K et al. (2001). "A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus". Diabetologia 44 (3): 373–6. doi:10.1007/s001250051629. PMID 11317671. 
  • Nibbelink M, Moulin K, Arnaud E et al. (2002). "Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells". J. Biol. Chem. 276 (50): 47291–5. doi:10.1074/jbc.M105658200. PMID 11572862. 
  • Echtay KS, Roussel D, St-Pierre J et al. (2002). "Superoxide activates mitochondrial uncoupling proteins". Nature 415 (6867): 96–9. doi:10.1038/415096a. PMID 11780125. 
  • Rousset S, del Mar Gonzalez-Barroso M, Gelly C et al. (2002). "A new polymorphic site located in the human UCP1 gene controls the in vitro binding of CREB-like factor". Int. J. Obes. Relat. Metab. Disord. 26 (5): 735–8. doi:10.1038/sj.ijo.0801973. PMID 12032762. 
  • Rim JS, Kozak LP (2002). "Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene". J. Biol. Chem. 277 (37): 34589–600. doi:10.1074/jbc.M108866200. PMID 12084707. 
  • Kieć-Wilk B, Wybrańska I, Malczewska-Malec M et al. (2003). "Correlation of the -3826A >G polymorphism in the promoter of the uncoupling protein 1 gene with obesity and metabolic disorders in obese families from southern Poland". J. Physiol. Pharmacol. 53 (3): 477–90. PMID 12375583. 
  • Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 

External links

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