Advertisement

Pflügers Archiv - European Journal of Physiology

, Volume 459, Issue 2, pp 269–275 | Cite as

The role of mitochondrial uncoupling proteins in lifespan

  • Marcelo O. Dietrich
  • Tamas L. Horvath
Integrative Physiology

Abstract

The increased longevity in modern societies raised the attention to biological interventions that could promote a healthy aging. Mitochondria are main organelles involved in the production of adenosine triphosphate (ATP), the energetic substrate for cellular biochemical reactions. The production of ATP occurs through the oxidative phosphorylation of intermediate substrates derived from the breakdown of lipids, sugars, and proteins. This process is coupled to production of oxygen reactive species (ROS) that in excess will have a deleterious role in cellular function. The damage promoted by ROS has been emphasized as one of the main processes involved in senescence. In the last decades, the discovery of specialized proteins in the mitochondrial inner membrane that promote the uncoupling of proton flux (named uncoupling proteins–UCPs) from the ATP synthase shed light on possible mechanisms implicated in the buffering of ROS and consequently in the process of aging. UCPs are responsible for a physiological uncoupling that leads to decrease in ROS production inside the mitochondria. Thus, induction of uncoupling through UCPs could decrease the cellular damage that occurs during aging due to excess of ROS. This review will focus on the evidence supporting these mechanisms.

Keywords

Aging Mitochondria Free radical Oxidative phosphorylation ATP 

Notes

Acknowledgements

MOD was partially supported by a fellowship from the Conselho Nacional de Pesquisa (CNPq), Brazil.

References

  1. 1.
    Andrews ZB, Horvath TL (2009) Uncoupling protein-2 regulates lifespan in mice. Am J Physiol Endocrinol Metab 296:E621–E627CrossRefPubMedGoogle Scholar
  2. 2.
    Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70:200–214CrossRefGoogle Scholar
  3. 3.
    Arechaga I, Ledesma A, Rial E (2001) The mitochondrial uncoupling protein UCP1: a gated pore. IUBMB Life 52:165–173CrossRefPubMedGoogle Scholar
  4. 4.
    Arsenijevic D, Onuma H, Pecqueur C et al (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26:435–439CrossRefPubMedGoogle Scholar
  5. 5.
    Asami DK, McDonald RB, Hagopian K et al (2008) Effect of aging, caloric restriction, and uncoupling protein 3 (UCP3) on mitochondrial proton leak in mice. Exp Gerontol 43:1069–1076CrossRefPubMedGoogle Scholar
  6. 6.
    Barja G (1998) Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci 854:224–238CrossRefPubMedGoogle Scholar
  7. 7.
    Barja G (1999) Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembranes 31:347–366CrossRefGoogle Scholar
  8. 8.
    Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581PubMedGoogle Scholar
  9. 9.
    Bevilacqua L, Ramsey JJ, Hagopian K et al (2004) Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. Am J Physiol Endocrinol Metab 286:E852–E861CrossRefPubMedGoogle Scholar
  10. 10.
    Bevilacqua L, Ramsey JJ, Hagopian K et al (2005) Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab 289:E429–E438CrossRefPubMedGoogle Scholar
  11. 11.
    Bishop NA, Guarente L (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8:835–844CrossRefPubMedGoogle Scholar
  12. 12.
    Boss O, Samec S, Paoloni-Giacobino A et al (1997) Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408:39–42CrossRefPubMedGoogle Scholar
  13. 13.
    Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811–820CrossRefPubMedGoogle Scholar
  14. 14.
    Caldeira da Silva CC, Cerqueira FM, Barbosa LF et al (2008) Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7:552–560CrossRefPubMedGoogle Scholar
  15. 15.
    Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMedGoogle Scholar
  16. 16.
    Conti B, Sanchez-Alavez M, Winsky-Sommerer R et al (2006) Transgenic mice with a reduced core body temperature have an increased life span. Science 314:825–828CrossRefPubMedGoogle Scholar
  17. 17.
    Cypess AM, Lehman S, Williams G et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517CrossRefPubMedGoogle Scholar
  18. 18.
    Diano S, Urbanski HF, Horvath B et al (2000) Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology 141:4226–4638CrossRefPubMedGoogle Scholar
  19. 19.
    Echtay KS, Roussel D, St-Pierre J et al (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99CrossRefPubMedGoogle Scholar
  20. 20.
    Echtay KS, Murphy MP, Smith RA et al (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277:47129–47135CrossRefPubMedGoogle Scholar
  21. 21.
    Feng J, Bussière F, Hekimi S (2001) Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell 1:633–644CrossRefPubMedGoogle Scholar
  22. 22.
    Fleury C, Neverova M, Collins S et al (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–272CrossRefPubMedGoogle Scholar
  23. 23.
    Fridell YW, Sánchez-Blanco A, Silvia BA, Helfand SL (2005) Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 1:145–152CrossRefPubMedGoogle Scholar
  24. 24.
    Gong DW, He Y, Karas M, Reitman M (1997) Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem 272:24129–24132CrossRefPubMedGoogle Scholar
  25. 25.
    Holzenberger M, Dupont J, Ducos B et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187CrossRefPubMedGoogle Scholar
  26. 26.
    Horvath TL, Warden CH, Hajos M et al (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19:10417–10427PubMedGoogle Scholar
  27. 27.
    Kim-Han JS, Reichert SA, Quick KL, Dugan LL (2001) BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production. J Neurochem 79:658–668CrossRefPubMedGoogle Scholar
  28. 28.
    Klingenberg M, Appel M (1989) The uncoupling protein dimer can form a disulfide cross-link between the mobile C-terminal SH groups. Eur J Biochem 180:123–131CrossRefPubMedGoogle Scholar
  29. 29.
    Kowaltowski AJ, Costa AD, Vercesi AE (1998) Activation of the potato plant uncoupling mitochondrial protein inhibits reactive oxygen species generation by the respiratory chain. FEBS Lett 425:213–216CrossRefPubMedGoogle Scholar
  30. 30.
    Krauss S, Zhang CY, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nature Rev Mol Cell Biol 6:248–261CrossRefGoogle Scholar
  31. 31.
    Lebovitz RM, Zhang H, Vogel H et al (1996) Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 93:9782–9787CrossRefPubMedGoogle Scholar
  32. 32.
    Lin SJ, Kaeberlein M, Andalis AA et al (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418:344–348CrossRefPubMedGoogle Scholar
  33. 33.
    Lockie SH, Müller TD, Tschöp MH (2009) Coupled with uncouplers: the curious case of lifespan. Am J Physiol Endocrinol Metab 296:E619–E620CrossRefPubMedGoogle Scholar
  34. 34.
    Mao W, Yu XX, Zhong A et al (1999) UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett 443:326–330CrossRefPubMedGoogle Scholar
  35. 35.
    McDonald RB, Walker KM, Warman DB et al (2008) Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice. Exp Gerontol 43:1061–1068CrossRefPubMedGoogle Scholar
  36. 36.
    Miroux B, Frossard V, Raimbault S et al (1993) 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 12:3739–3745PubMedGoogle Scholar
  37. 37.
    Murphy MP, Echtay KS, Blaikie FH et al (2003) Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. J Biol Chem 278:48534–48545CrossRefPubMedGoogle Scholar
  38. 38.
    Nègre-Salvayre A, Hirtz C, Carrera G et al (1997) A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 11:809–815PubMedGoogle Scholar
  39. 39.
    Nicholls DG, Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev 64:1–64PubMedGoogle Scholar
  40. 40.
    Pecqueur C, Alves-Guerra MC, Gelly C et al (1998) Distribution of the uncoupling protein 2 mRNA in the mouse brain. J Comp Neurol 397:549–560CrossRefGoogle Scholar
  41. 41.
    Pecqueur C, Alves-Guerra MC, Gelly C et al (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem 276:8705–8712CrossRefPubMedGoogle Scholar
  42. 42.
    Richard D, Rivest R, Huang Q et al (1998) Distribution of the uncoupling protein 2 mRNA in the mouse brain. J Comp Neurol 397:549–560CrossRefPubMedGoogle Scholar
  43. 43.
    Richard D, Clavel S, Huang Q et al (2001) Uncoupling protein 2 in the brain: distribution and function. Biochem Soc Trans 29:812–817CrossRefPubMedGoogle Scholar
  44. 44.
    Ricquier D, Bouillaud F, Miroux B (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem 276:8705–8712CrossRefPubMedGoogle Scholar
  45. 45.
    Sanchis D, Fleury C, Chomiki N et al (1998) BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 273:34611–34615CrossRefPubMedGoogle Scholar
  46. 46.
    Sivitz WI, Fink BD, Donohoue PA (1999) Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression. Endocrinology 140:1511–1519CrossRefPubMedGoogle Scholar
  47. 47.
    Skulachev VP (1998) Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1363:100–124CrossRefPubMedGoogle Scholar
  48. 48.
    Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63CrossRefPubMedGoogle Scholar
  49. 49.
    Speakman JR, Talbot DA, Selman C et al (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3:87–95CrossRefPubMedGoogle Scholar
  50. 50.
    Tahara EB, Barros MH, Oliveira GA et al (2007) Dihydrolipoyl dehydrogenase as a source of reactive oxygen species inhibited by caloric restriction and involved in Saccharomyces cerevisiae aging. FASEB J 21:274–283CrossRefPubMedGoogle Scholar
  51. 51.
    Vidal-Puig A, Solanes G, Grujic D et al (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 235:79–82CrossRefPubMedGoogle Scholar
  52. 52.
    van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508CrossRefPubMedGoogle Scholar
  53. 53.
    Yamada S, Isojima Y, Yamatodani A, Nagai K (2000) Uncoupling protein 2 influences dopamine secretion in PC12h cells. J Neurochem 87:461–469CrossRefGoogle Scholar
  54. 54.
    Zhang CY, Baffy G, Perret P et al (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Section of Comparative MedicineYale University School of MedicineNew HavenUSA
  2. 2.Programa de Pós-graduação em Bioquímica, Department of BiochemistryUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Departments of Obstetrics, Gynecology and Reproductive SciencesYale University School of MedicineNew HavenUSA
  4. 4.NeurobiologyYale University School of MedicineNew HavenUSA

Personalised recommendations