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
The molecular mechanism of UCP1 mediated uncoupling is reasonably well understood; UCP1 provides an alternative pathway by which protons can reenter the mitochondrial matrix, short-circuiting the 'proton circuit' linking the respiratory chain to the ATP synthase (which generates ATP for the cell) and allowing respiration (and hence heat production) to proceed in the absence of ATP synthesis. 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 fat 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 that are liberated by the following pathway: 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 nucleodides (GDP, 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 19792 and was first cloned in 1988.34
Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. 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. 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, http://www.jbc.org/cgi/content/abstract/263/25/12274.
- ^ 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 Pt 2: 161–79. 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. PMID 9398715.
- Jezek P, Urbánková E (2000). "Specific sequence of motifs of mitochondrial uncoupling proteins". IUBMB Life 49 (1): 63–70. 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. PMID 12477932.
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