Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The mitochondrial uncoupling-protein homologues

Nature Reviews Molecular Cell Biology volume 6, pages 248–261 (2005)Cite this article

Key Points

  • Uncoupling proteins (UCPs) belong to the superfamily of mitochondrial-inner-membrane anion-carrier proteins.

  • UCP1, the classic uncoupling protein, is exclusively and abundantly expressed in brown adipose tissue. Its physiological role is to mediate a regulated, thermogenic proton leak across the mitochondrial inner membrane.

  • UCP2 and UCP3 were recently isolated as homologues of brown-adipose UCP1. UCP2 and UCP3 also mediate proton leak, but they do not have a thermogenic role, and their tissue distribution is more diverse compared with UCP1. The physiological function of UCP2 and UCP3 is not known, but it has been speculated that they might control the production of reactive oxygen species.

  • Recent work has shown that the UCP homologues are activated by a superoxide-dependent mechanism. This observation led to the suggestion of a feedback mechanism which controls the production of reactive oxygen species; however, the importance of the UCP homologues in cellular antioxidant defence is not clear at this point.

  • Although the physiological functions of UCP2 and UCP3 remain uncertain, it has been shown that UCP2, by virtue of its proton-leak activity, has an important role in the pathophysiology of type-2 diabetes. In particular, hyperglycaemia causes a pathological, superoxide-dependent activation of UCP2 in pancreatic islets, which, in turn, causes loss of glucose-stimulated insulin secretion.

  • Further work is required to elucidate the physiological roles and regulation of UCP2 and UCP3, and to understand, at a molecular level, how they mediate proton leak. This will have implications for many pathologies and diseases: for example, targeted inhibition of UCP2 should be a useful tool in the treatment of pancreatic-β-cell dysfunction and type-2 diabetes.

Abstract

Uncoupling protein(UCP)1 is an integral membrane protein that is located in the mitochondrial inner membrane of brown adipocytes. Its physiological role is to mediate a regulated, thermogenic proton leak. UCP2 and UCP3 are recently identified UCP1 homologues. They also mediate regulated proton leak, and might function to control the production of superoxide and other downstream reactive oxygen species. However, their role in normal physiology remains unknown. Recent studies have shown that UCP2 has an important part in the pathogenesis of type-2 diabetes. The obscure roles of the UCP homologues in normal physiology, together with their emerging role in pathophysiology, provide exciting potential for further investigation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Substrate oxidation and oxidative phosphorylation in mammalian cells.
Figure 2: Two models for free-fatty-acid-dependent proton translocation by UCP1.
Figure 3: Superoxide activation of UCP2 — a feedback loop.
Figure 4: UCP2 and pancreatic-β-cell dysfunction.

Similar content being viewed by others

References

  1. Nicholls, D. G. & Ferguson, S. J. Bioenergetics 3 (Academic Press, London, 2002).

  2. Stuart, J. A., Cadenas, S., Jekabsons, M. B., Roussel, D. & Brand, M. D. Mitochondrial proton leak and the uncoupling protein 1 homologues. Biochim. Biophys. Acta 1504, 144–158 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Papa, S. & Skulachev, V. P. Reactive oxygen species, mitochondria, apoptosis and aging. Mol. Cell. Biochem. 174, 305–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Borecky, J., Maia, I. G. & Arruda, P. Mitochondrial uncoupling proteins in mammals and plants. Biosci. Rep. 21, 201–212 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Ledesma, A., de Lacoba, M. G. & Rial, E. The mitochondrial uncoupling proteins. Genome Biol. 3, REVIEWS3015 (2002).

  6. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Gimeno, R. E. et al. Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. Diabetes 46, 900–906 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Boss, O. et al. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 408, 39–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Vidal-Puig, A., Solanes, G., Grujic, D., Flier, J. S. & Lowell, B. B. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem. Biophys. Res. Commun. 235, 79–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Gong, D. W., He, Y., Karas, M. & Reitman, M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β3-adrenergic agonists, and leptin. J. Biol. Chem. 272, 24129–24132 (1997). References 6–10 are the original papers that describe the discovery of UCP2 and UCP3.

    Article  CAS  PubMed  Google Scholar 

  11. Klingenberg, M. & Appel, M. The uncoupling protein dimer can form a disulfide cross-link between the mobile C-terminal SH groups. Eur. J. Biochem. 180, 123–131 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Nicholls, D. G. & Locke, R. M. Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1–64 (1984). A classic review of UCP1 and BAT biochemistry and physiology.

    Article  CAS  PubMed  Google Scholar 

  13. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004). A comprehensive, up-to-date review of BAT physiology, which includes a detailed discussion of the role of UCP1 in thermogenesis.

    Article  CAS  PubMed  Google Scholar 

  14. Marette, A. & Bukowiecki, L. J. Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes. Am. J. Physiol. 257, C714–C721 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Omatsu-Kanbe, M. & Kitasato, H. Insulin and noradrenaline independently stimulate the translocation of glucose transporters from intracellular stores to the plasma membrane in mouse brown adipocytes. FEBS Lett. 314, 246–250 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Houstek, J. & Drahota, Z. Purification and properties of mitochondrial adenosine triphosphatase of hamster brown adipose tissue. Biochim. Biophys. Acta 484, 127–139 (1977).

    Article  CAS  PubMed  Google Scholar 

  17. Cannon, B. & Vogel, G. The mitochondrial ATPase of brown adipose tissue. Purification and comparison with the mitochondrial ATPase from beef heart. FEBS Lett. 76, 284–289 (1977).

    Article  CAS  PubMed  Google Scholar 

  18. Klingenberg, M. & Huang, S. G. Structure and function of the uncoupling protein from brown adipose tissue. Biochim. Biophys. Acta 1415, 271–296 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Winkler, E. & Klingenberg, M. Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein. J. Biol. Chem. 269, 2508–2515 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Garlid, K. D., Jaburek, M. & Jezek, P. The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett. 438, 10–14 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Skulachev, V. P. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett. 294, 158–162 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Jezek, P., Orosz, D. E., Modriansky, M. & Garlid, K. D. Transport of anions and protons by the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids. A new look at old hypotheses. J. Biol. Chem. 269, 26184–26190 (1994). References 21 and 22 outline the development of the fatty-acid-cycling model of UCP function.

    Article  CAS  PubMed  Google Scholar 

  23. Garlid, K. D., Orosz, D. E., Modriansky, M., Vassanelli, S. & Jezek, P. On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J. Biol. Chem. 271, 2615–2620 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Jaburek, M., Varecha, M., Jezek, P. & Garlid, K. D. Alkylsulfonates as probes of uncoupling protein transport mechanism. Ion pair transport demonstrates that direct H+ translocation by UCP1 is not necessary for uncoupling. J. Biol. Chem. 276, 31897–31905 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Gonzalez-Barroso, M. M., Fleury, C., Bouillaud, F., Nicholls, D. G. & Rial, E. The uncoupling protein UCP1 does not increase the proton conductance of the inner mitochondrial membrane by functioning as a fatty acid anion transporter. J. Biol. Chem. 273, 15528–15532 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Garlid, K. D., Jaburek, M., Jezek, P. & Varecha, M. How do uncoupling proteins uncouple? Biochim. Biophys. Acta 1459, 383–389 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Garlid, K. D., Jaburek, M. & Jezek, P. Mechanism of uncoupling protein action. Biochem. Soc. Trans 29, 803–806 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Rial, E., Aguirregoitia, E., Jimenez-Jimenez, J. & Ledesma, A. Alkylsulfonates activate the uncoupling protein UCP1: implications for the transport mechanism. Biochim. Biophys. Acta 1608, 122–130 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Echtay, K. S., Winkler, E. & Klingenberg, M. Coenzyme Q is an obligatory cofactor for uncoupling protein function. Nature 408, 609–613 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Nicholls, D. G. Brown adipose tissue mitochondria. Biochim. Biophys. Acta 549, 1–29 (1979).

    Article  CAS  PubMed  Google Scholar 

  31. Jezek, P. & Garlid, K. D. New substrates and competitive inhibitors of the Cl− translocating pathway of the uncoupling protein of brown adipose tissue mitochondria. J. Biol. Chem. 265, 19303–19311 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Heaton, G. M., Wagenvoord, R. J., Kemp, A. Jr & Nicholls, D. G. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur. J. Biochem. 82, 515–521 (1978). A classic paper describing identification of UCP1.

    Article  CAS  PubMed  Google Scholar 

  33. Nicholls, D. G. A history of UCP1. Biochem. Soc. Trans 29, 751–755 (2001). A mini-review giving an historic perspective on the discovery of UCP1.

    Article  CAS  PubMed  Google Scholar 

  34. Nicholls, D. G. Hamster brown-adipose-tissue mitochondria. Purine nucleotide control of the ion conductance of the inner membrane, the nature of the nucleotide binding site. Eur. J. Biochem. 62, 223–228 (1976).

    Article  CAS  PubMed  Google Scholar 

  35. Hagen, T., Zhang, C. Y., Vianna, C. R. & Lowell, B. B. Uncoupling proteins 1 and 3 are regulated differently. Biochemistry 39, 5845–5851 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Sivitz, W. I., Fink, B. D. & Donohoue, P. A. Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression. Endocrinology 140, 1511–1519 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Pecqueur, C. et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J. Biol. Chem. 276, 8705–8712 (2001). References 36 and 37 clearly show that the amount of UCP2 mRNA, in different tissues and in different physiological states, does not predict the amount or presence of UCP2 protein.

    Article  CAS  PubMed  Google Scholar 

  38. Boss, O., Muzzin, P. & Giacobino, J. P. The uncoupling proteins, a review. Eur. J. Endocrinol. 139, 1–9 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Ricquier, D. & Bouillaud, F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem. J. 345, 161–179 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nedergaard, J. & Cannon, B. The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp. Physiol. 88, 65–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Jaburek, M. & Garlid, K. D. Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. J. Biol. Chem. 278, 25825–25831 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Echtay, K. S., Winkler, E., Frischmuth, K. & Klingenberg, M. Uncoupling proteins 2 and 3 are highly active H+ transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone). Proc. Natl Acad. Sci. USA 98, 1416–1421 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Clapham, J. C. et al. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415–418 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Stuart, J. A., Harper, J. A., Brindle, K. M., Jekabsons, M. B. & Brand, M. D. A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem. J. 356, 779–789 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stuart, J. A., Harper, J. A., Brindle, K. M., Jekabsons, M. B. & Brand, M. D. Physiological levels of mammalian uncoupling protein 2 do not uncouple yeast mitochondria. J. Biol. Chem. 276, 18633–18639 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Harper, J. A. et al. Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria. Biochem. J. 361, 49–56 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cadenas, S. et al. The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J. Biol. Chem. 277, 2773–2778 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002). Seminal work on the regulation of uncoupling proteins by superoxide.

    Article  CAS  PubMed  Google Scholar 

  49. Krauss, S., Zhang, C. Y. & Lowell, B. B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc. Natl Acad. Sci. USA 99, 118–122 (2002). Shows that endogenous UCP2 mediates proton leak in intact cells.

    Article  CAS  PubMed  Google Scholar 

  50. Krauss, S. et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction. J. Clin. Invest. 112, 1831–1842 (2003). Highlights the significance of superoxide-mediated activation of UCP2 in β-cell pathophysiology and type-2 diabetes. Shows that increased UCP2 activity causes hyperglycaemia-induced loss of glucose sensing in β-cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gong, D. W. et al. Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J. Biol. Chem. 275, 16251–16257 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Vidal-Puig, A. J. et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J. Biol. Chem. 275, 16258–16266 (2000). Shows that endogenous UCP3 has a role in limiting superoxide production.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 105, 745–755 (2001). Shows the critical role of UCP2 in vivo in the pathophysiology of β-cell dysfunction and type-2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  54. Cline, G. W. et al. In vivo effects of uncoupling protein-3 gene disruption on mitochondrial energy metabolism. J. Biol. Chem. 276, 20240–20244 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Murphy, M. P. et al. Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from α-phenyl-N-tert-butylnitrone. J. Biol. Chem. 278, 48534–48545 (2003). Outlines a basic model of the pathway by which superoxide might activate UCP1 and its homologues.

    Article  CAS  PubMed  Google Scholar 

  56. Echtay, K. S., Murphy, M. P., Smith, R. A., Talbot, D. A. & Brand, M. D. Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J. Biol. Chem. 277, 47129–47135 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Considine, M. J. et al. Superoxide stimulates a proton leak in potato mitochondria that is related to the activity of uncoupling protein. J. Biol. Chem. 278, 22298–22302 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Echtay, K. S. et al. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 22, 4103–4110 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zackova, M., Skobisova, E., Urbankova, E. & Jezek, P. Activating ω-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3. J. Biol. Chem. 278, 20761–20769 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Jaburek, M. et al. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J. Biol. Chem. 274, 26003–26007 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997). Shows that UCP1 is responsible for cold-exposure-induced, non-shivering thermogenesis.

    Article  CAS  PubMed  Google Scholar 

  62. Arsenijevic, D. et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genet. 26, 435–439 (2000). First report of a UCP2 -knockout-mouse model; shows that endogenous UCP2 protein has a role in limiting ROS production.

    Article  CAS  PubMed  Google Scholar 

  63. Bezaire, V., Hofmann, W., Kramer, J. K., Kozak, L. P. & Harper, M. E. Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3−/− and wild-type mice. Am. J. Physiol. Endocrinol. Metab. 281, E975–E982 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Hoerter, J. et al. Mitochondrial uncoupling protein 1 expressed in the heart of transgenic mice protects against ischemic-reperfusion damage. Circulation 110, 528–533 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Mills, E. M., Banks, M. L., Sprague, J. E. & Finkel, T. Pharmacology: uncoupling the agony from ecstasy. Nature 426, 403–404 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Schrauwen, P. et al. Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J. 17, 2272–2274 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Himms-Hagen, J. & Harper, M. E. Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp. Biol. Med. (Maywood) 226, 78–84 (2001).

    Article  CAS  Google Scholar 

  68. Alexson, S. E. & Nedergaard, J. A novel type of short- and medium-chain acyl-CoA hydrolases in brown adipose tissue mitochondria. J. Biol. Chem. 263, 13564–13571 (1988).

    Article  CAS  PubMed  Google Scholar 

  69. Boss, O., Hagen, T. & Lowell, B. B. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49, 143–156 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Gong, D. W., He, Y. & Reitman, M. L. Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes. Biochem. Biophys. Res. Commun. 256, 27–32 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Argyropoulos, G. et al. Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. J. Clin. Invest. 102, 1345–1351 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chung, W. K. et al. Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis. Diabetes 48, 1890–1895 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Chung, W. K. et al. The long isoform uncoupling protein-3 (UCP3L) in human energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 23 (Suppl. 6), S49–S50 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Korshunov, S. S., Skulachev, V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15–18 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Negre-Salvayre, A. et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 11, 809–815 (1997). First formulation of the hypothesis that UCP homologues regulate superoxide production.

    Article  CAS  PubMed  Google Scholar 

  76. Duval, C. et al. Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells. Biochem. Cell Biol. 80, 757–764 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Brand, M. D. et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic. Biol. Med. 37, 755–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Talbot, D. A., Lambert, A. J. & Brand, M. D. Production of endogenous matrix superoxide from mitochondrial complex I leads to activation of uncoupling protein 3. FEBS Lett. 556, 111–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Brand, M. D. et al. Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochem. J. 368, 597–603 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Teshima, Y., Akao, M., Jones, S. P. & Marban, E. Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ. Res. 93, 192–200 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Mattiasson, G. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med. 9, 1062–1068 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Diano, S. et al. Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144, 5014–5021 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. de Bilbao, F. et al. Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. J. Neurochem. 89, 1283–1292 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Ashcroft, F. M. & Gribble, F. M. ATP-sensitive K+ channels and insulin secretion: their role in health and disease. Diabetologia 42, 903–919 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Matschinsky, F. M., Glaser, B. & Magnuson, M. A. Pancreatic β-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47, 307–315 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Gembal, M., Detimary, P., Gilon, P., Gao, Z. Y. & Henquin, J. C. Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells. J. Clin. Invest. 91, 871–880 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Takahashi, N. et al. Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic β cells. Proc. Natl Acad. Sci. USA 96, 760–765 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chan, C. B. et al. Increased uncoupling protein-2 levels in β-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 50, 1302–1310 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Chan, C. B. et al. Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48, 1482–1486 (1999). Shows that the forced overexpression of UCP2 in pancreatic β-cells causes loss of glucose sensing.

    Article  CAS  PubMed  Google Scholar 

  90. Joseph, J. W. et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51, 3211–3219 (2002). Shows that the absence of UCP2 protects against high-fat-diet-induced β-cell dysfunction.

    Article  CAS  PubMed  Google Scholar 

  91. Winzell, M. S. et al. Pancreatic β-cell lipotoxicity induced by overexpression of hormone-sensitive lipase. Diabetes 52, 2057–2065 (2003).

    Article  PubMed  Google Scholar 

  92. Laybutt, D. R. et al. Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J. Biol. Chem. 277, 10912–10921 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Kassis, N. et al. Correlation between pancreatic islet uncoupling protein-2 (UCP2) mRNA concentration and insulin status in rats. Int. J. Exp. Diabetes Res. 1, 185–193 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bindokas, V. P. et al. Visualizing superoxide production in normal and diabetic rat islets of langerhans. J. Biol. Chem. 278, 9796–9801 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Lameloise, N., Muzzin, P., Prentki, M. & Assimacopoulos-Jeannet, F. Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes 50, 803–809 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Diraison, F. et al. Over-expression of sterol regulatory element binding protein-1c in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside. Biochem. J. 378, 769–778 (2003).

    Article  Google Scholar 

  97. Yamashita, T. et al. Role of UCP-2 up-regulation and TG accumulation in impaired glucose-stimulated insulin secretion in a β-cell lipotoxicity model overexpressing SREBP-1c. Endocrinology 145, 3566–3577 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Koshkin, V., Wang, X., Scherer, P. E., Chan, C. B. & Wheeler, M. B. Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids. J. Biol. Chem. 278, 19709–19715 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Joseph, J. W. et al. Free fatty acid induced β-cell defects are dependent on uncoupling protein 2 expression. J. Biol. Chem. 279, 51049–51056 (2004). Shows that the absence of UCP2 protects against fatty-acid-induced β-cell dysfunction.

    Article  CAS  PubMed  Google Scholar 

  100. Miwa, I., Ichimura, N., Sugiura, M., Hamada, Y. & Taniguchi, S. Inhibition of glucose-induced insulin secretion by 4-hydroxy-2-nonenal and other lipid peroxidation products. Endocrinology 141, 2767–2772 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Poitout, V. & Robertson, R. P. Minireview: Secondary β-cell failure in type 2 diabetes — a convergence of glucotoxicity and lipotoxicity. Endocrinology 143, 339–342 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Pebay-Peyroula, E. et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426, 39–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Miroux, B., Frossard, V., Raimbault, S., Ricquier, D. & Bouillaud, F. The topology of the brown adipose tissue mitochondrial uncoupling protein determined with antibodies against its antigenic sites revealed by a library of fusion proteins. EMBO J. 12, 3739–3745 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Arechaga, I., Ledesma, A. & Rial, E. The mitochondrial uncoupling protein UCP1: a gated pore. IUBMB Life 52, 165–173 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Klingenberg, M., Echtay, K. S., Bienengraeber, M., Winkler, E. & Huang, S. G. Structure-function relationship in UCP1. Int. J. Obes. Relat. Metab. Disord. 23 (Suppl. 6), S24–S29 (1999). Comprehensive review of UCP1-mediated proton transport, summarizing the work that led to the formulation of the proton-buffering model.

    Article  CAS  PubMed  Google Scholar 

  106. Modriansky, M., Murdza-Inglis, D. L., Patel, H. V., Freeman, K. B. & Garlid, K. D. Identification by site-directed mutagenesis of three arginines in uncoupling protein that are essential for nucleotide binding and inhibition. J. Biol. Chem. 272, 24759–24762 (1997). Important paper showing the critical role of arginine residues in mediating inhibition of UCP1 by purine nucleotides.

    Article  CAS  PubMed  Google Scholar 

  107. Esterbauer, H. et al. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nature Genet. 28, 178–183 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Krempler, F. et al. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 51, 3331–3335 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Sesti, G. et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 52, 1280–1283 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Sasahara, M. et al. Uncoupling protein 2 promoter polymorphism −866G/A affects its expression in β-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 53, 482–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Maechler, P. & Wollheim, C. B. Mitochondrial function in normal and diabetic β-cells. Nature 414, 807–812 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Porterfield, D. M. et al. Oxygen consumption oscillates in single clonal pancreatic β-cells (HIT). Diabetes 49, 1511–1516 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Huang, X. & Miller, W. E. A time-efficient, linear-space local similarity algorithm. Adv. Appl. Math. 12, 337–357 (1991).

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank E. Rial and J. St. Pierre for discussions. This work was supported by grants from the National Institutes of Health (to B.B.L.), and a Junior Faculty Award by the American Diabetes Association and an Outstanding Young Scientist Award by the National Natural Science Foundation of China (to C.-Y.Z.).

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Stefan Krauss, Chen-Yu Zhang & Bradford B. Lowell

  2. Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Stefan Krauss

  3. National Pharmaceutical & Medical Key Laboratory, School of Life Science, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, China

    Chen-Yu Zhang

Authors
  1. Stefan Krauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen-Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bradford B. Lowell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bradford B. Lowell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Swiss-Prot

UCP1

UCP2

UCP3

UCP4

UCP5

SIM - Local similarity program

Glossary

OXIDATIVE PHOSPHORYLATION

A mitochondrial process that links the oxidation of fuel substrates to the generation of high-energy phosphates (ATP) that can be used by the cell for energy-consuming pathways.

BROWN ADIPOSE TISSUE (BAT)

A tissue that consists of brown adipocytes and is specialised in mediating thermogenesis (that is, the generation of heat).

PROTON LEAK

Movement of the proton (H+) across the mitochondrial inner membrane, which either occurs spontaneously or is mediated by proteins. Proton leak can occur nonspecifically at the protein–lipid interface; alternatively, proton leak mediated by proteins such as UCPs can occur due to direct or indirect transport of protons.

REACTIVE OXYGEN SPECIES

(ROS). Reactive intermediates that are derived from oxygen. ROS can be molecules (for example, hydrogen peroxide), radicals (for example, hydroxyl radicals), or ions (for example, hydroxyl ions).

ISLETS OF LANGERHANS

Clusters of cells that comprise the endocrine portion of the pancreas. Pancreatic islets consist of three main cell types: α-cells that secrete glucagon, β-cells that secrete insulin and δ-cells that secrete somatostatin.

TYPE-2 DIABETES

Abnormal conditions such as obesity and hyperglycaemia cause disturbances in metabolism and gene expression, which lead to insulin resistance and pancreatic-β-cell dysfunction. The combination of both insulin resistance and β-cell dysfunction causes type-2 diabetes.

β-ADRENERGIC RECEPTORS

Membrane-bound G-protein-coupled receptors, the extracellular domains of which bind noradrenaline and adrenaline. In BAT, binding of noradrenaline to β-adrenergic receptors triggers the events that lead to thermogenesis.

LIPOLYSIS

The release of fatty acids and glycerol from triacylglyceride (lipid) stores, which is mediated by hormone-sensitive lipase.

WHITE ADIPOCYTES

The cells of white adipose tissue, a main site of lipid storage.

PROTEOLIPOSOMES

A model system for the study of biological membranes and membrane-bound proteins (for example, transport proteins). Proteoliposomes lack the complexity of cellular environments and are easily amenable to adjustments of lipid and protein content, as well as specific assay conditions (such as pH and ionic strength).

CRISTAE

The folds that are formed by the mitochondrial inner membrane.

RESPIRATORY QUOTIENT

(RQ). The ratio between the amount of exhaled CO2 and the amount of inhaled oxygen. The RQ is different for each of the main fuels that are usually metabolized (that is, carbohydrates, fats and proteins). This allows the identification of fuels that are metabolized under various conditions.

ISCHAEMIA/REPERFUSION INJURY

Ischaemia occurs after the disruption of blood and oxygen supply to tissues such as the heart and the brain. When blood and oxygen supply is re-established, a paradoxical progressive destruction of cells can occur that is known as reperfusion injury.

POLYMORPHISMS

The multiple allelic forms of genes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krauss, S., Zhang, CY. & Lowell, B. The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6, 248–261 (2005). https://doi.org/10.1038/nrm1592

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1592

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing