Cellular and Molecular Life Sciences

, Volume 74, Issue 21, pp 3897–3911 | Cite as

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin

  • Giuseppe Paradies
  • Valeria Paradies
  • Francesca M. Ruggiero
  • Giuseppe Petrosillo
Multi-author review


Aging is a biological process characterized by progressive decline in physiological functions, increased oxidative stress, reduced capacity to respond to stresses, and increased risk of contracting age-associated disorders. Mitochondria are referred to as the powerhouse of the cell through their role in the oxidative phosphorylation to generate ATP. These organelles contribute to the aging process, mainly through impairment of electron transport chain activity, opening of the mitochondrial permeability transition pore and increased oxidative stress. These events lead to damage to proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis and in mitochondrial membrane stability and dynamics. Cardiolipin alterations are associated with mitochondrial bienergetics decline in multiple tissues in a variety of physiopathological conditions, as well as in the aging process. Melatonin, the major product of the pineal gland, is considered an effective protector of mitochondrial bioenergetic function. Melatonin preserves mitochondrial function by preventing cardiolipin oxidation and this may explain, at least in part, the protective role of this compound in mitochondrial physiopathology and aging. Here, mechanisms through which melatonin exerts its protective role against mitochondrial dysfunction associated with aging and age-associated disorders are discussed.


Melatonin Mitochondrial bioenergetics Cardiolipin Aging 


  1. 1.
    Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J. Gerontol 11:298–300PubMedCrossRefGoogle Scholar
  2. 2.
    Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147PubMedCrossRefGoogle Scholar
  3. 3.
    Miquel J, Economos AC, Fleming J et al (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591PubMedCrossRefGoogle Scholar
  4. 4.
    Pak JW, Herbst A, Bua E et al (2003) Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging. Aging Cell 2:1–7PubMedCrossRefGoogle Scholar
  5. 5.
    Wei YH (1992) Mitochondrial DNA alterations as ageing-associated molecular events. Mutat Res 275:145–155PubMedCrossRefGoogle Scholar
  6. 6.
    Richter C (1995) Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 27:647–653PubMedCrossRefGoogle Scholar
  7. 7.
    Linnane AW, Marzuki S, Ozawa T et al (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1:642–645PubMedCrossRefGoogle Scholar
  8. 8.
    Judge S, Leeuwenburgh C (2007) Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol Cell Physiol 292:C1983–C1992PubMedCrossRefGoogle Scholar
  9. 9.
    Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 5:59–63CrossRefGoogle Scholar
  10. 10.
    Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581PubMedGoogle Scholar
  11. 11.
    Hayakawa M, Hattori K, Sugiyama S et al (1992) Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochem Biophys Res Commun 189:979–985PubMedCrossRefGoogle Scholar
  12. 12.
    Paradies G, Ruggiero FM, Petrosillo G et al (1996) Age-dependent impairment of mitochondrial function in rat heart tissue: effect of pharmacological agents. Ann NY Acad Sci 786:252–263PubMedCrossRefGoogle Scholar
  13. 13.
    Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Lesnefsky EJ, Moghaddas S, Tandler B et al (2001) Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33:1065–1089PubMedCrossRefGoogle Scholar
  15. 15.
    Kauppila TE, Kauppila JH, Larsson NG (2017) Mammalian mitochondria and aging: an update. Cell Metab 25:57–71PubMedCrossRefGoogle Scholar
  16. 16.
    Ramis MR, Esteban S, Miralles A et al (2015) Protective effects of melatonin and mitochondria-targeted antioxidants against oxidative stress: a review. Curr Med Chem 22:2690–2711PubMedCrossRefGoogle Scholar
  17. 17.
    Gruber J, Fong S, Chen CB et al (2013) Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv 31:563–592PubMedCrossRefGoogle Scholar
  18. 18.
    Skulachev VP, Anisimov VN, Antonenko YN (2009) An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta 1787:437–461PubMedCrossRefGoogle Scholar
  19. 19.
    Hardeland R, Pandi-Perumal SR, Cardinali DP (2006) Melatonin. Int J Biochem Cell Biol 3:313–316CrossRefGoogle Scholar
  20. 20.
    Tan DX, Manchester LC, Terron MP et al (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 1:28–42CrossRefGoogle Scholar
  21. 21.
    Tan DX, Reiter RJ, Manchester LC et al (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–197PubMedCrossRefGoogle Scholar
  22. 22.
    Reiter RJ, Paredes SD, Korkmaz A et al (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip Toxicol 2:137–149Google Scholar
  23. 23.
    Reiter RJ, Mayo JC, Tan DX et al (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61:253–278PubMedCrossRefGoogle Scholar
  24. 24.
    Venegas C, García JA, Escames G et al (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227PubMedCrossRefGoogle Scholar
  25. 25.
    Leon J, Acuña-Castroviejo D, Sainz RM et al (2004) Melatonin and mitochondrial function. Life Sci 7:765–790CrossRefGoogle Scholar
  26. 26.
    Paradies G, Petrosillo G, Paradies V et al (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48:297–310PubMedCrossRefGoogle Scholar
  27. 27.
    Paradies G, Paradies V, Ruggiero FM et al (2015) Protective role of melatonin in mitochondrial dysfunction and related disorders. Arch Toxicol 89:923–939PubMedCrossRefGoogle Scholar
  28. 28.
    Acuña Castroviejo D, López LC, Escames G et al (2011) Melatonin–mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240PubMedCrossRefGoogle Scholar
  29. 29.
    Manchester LC, Coto-Montes A, Boga JA et al (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59:403–419PubMedCrossRefGoogle Scholar
  30. 30.
    Tan DX, Manchester LC, Qin L et al (2016) Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci 17:2124PubMedCentralCrossRefGoogle Scholar
  31. 31.
    Navarro-Alarcón M, Ruiz-Ojeda FJ, Blanca-Herrera RM et al (2014) Melatonin and metabolic regulation: a review. Food Funct 5:2806–2832PubMedCrossRefGoogle Scholar
  32. 32.
    Hardeland R, Cardinali DP, Brown GM et al (2015) Melatonin and brain inflammaging. Prog Neurobiol 128:46–63CrossRefGoogle Scholar
  33. 33.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P (2012) The role of melatonin in acute myocardial infarction. Front Biosci 17:2433–2441CrossRefGoogle Scholar
  34. 34.
    Favero G, Franceschetti L, Buffoli B et al (2017) Melatonin: protection against age-related cardiac pathology. Ageing Res Rev 35:336–349PubMedCrossRefGoogle Scholar
  35. 35.
    Yang Y, Sun Y, Yi W et al (2014) A review of melatonin as a suitable antioxidant against myocardial ischemia–reperfusion injury and clinical heart diseases. J Pineal Res 57:357–366PubMedCrossRefGoogle Scholar
  36. 36.
    Bondy SC, Sharman EH (2007) Melatonin and the aging brain. Neurochem Int 50:571–580PubMedCrossRefGoogle Scholar
  37. 37.
    Escames G, López A, García JA et al (2010) The role of mitochondria in brain aging and the effects of melatonin. Curr Neuropharmacol 3:182–193CrossRefGoogle Scholar
  38. 38.
    García JJ, López-Pingarrón L, Almeida-Souza P et al (2014) Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J Pineal Res 56:225–237PubMedCrossRefGoogle Scholar
  39. 39.
    Hoch FL (1992) Cardiolipins and biomembrane function. Biochim Biophys Acta 1113:71–133PubMedCrossRefGoogle Scholar
  40. 40.
    Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65:2493–2506PubMedCrossRefGoogle Scholar
  41. 41.
    Ren M, Phoon CK, Schlame M (2014) Metabolism and function of mitochondrial cardiolipin. Prog Lipid Res 55:1–16PubMedCrossRefGoogle Scholar
  42. 42.
    Paradies G, Paradies V, De Benedictis V et al (2014) Functional role of cardiolipin in mitochondrial bioenergetics. Biochim Biophys Acta 1837:408–417PubMedCrossRefGoogle Scholar
  43. 43.
    Paradies G, Paradies V, Ruggiero et al (2014) Cardiolipin and mitochondrial function in health and disease. Antioxid Redox Signal 20:1925–1953PubMedCrossRefGoogle Scholar
  44. 44.
    Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovsky DA, Wipf P, Kochanek PM, Greenberger JS, Pitt B, Shvedova AA, Borisenko G (2009) Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med 11:1439–1453CrossRefGoogle Scholar
  45. 45.
    Musatov A, Robinson NC (2012) Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase. Free Radic Res 46:1313–1326PubMedCrossRefGoogle Scholar
  46. 46.
    Mileykovskaya E, Dowhan W (2014) Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes. Chem Phys Lipids 179:42–48PubMedCrossRefGoogle Scholar
  47. 47.
    Claypool SM (2009) Cardiolipin, a critical determinant of mitochondrial carrier protein assembly and function. Biochim Biophys Acta 1788:2059–2068PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292:C33–C44PubMedCrossRefGoogle Scholar
  49. 49.
    Paradies G, Petrosillo G, Paradies et al (2009) Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 45:643–650PubMedCrossRefGoogle Scholar
  50. 50.
    Petrosillo G, Moro N, Ruggiero FM et al (2009) Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release. Free Radic Biol Med 47:969–974PubMedCrossRefGoogle Scholar
  51. 51.
    Petrosillo G, Fattoretti P, Matera M et al (2008) Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res 11:935–943PubMedCrossRefGoogle Scholar
  52. 52.
    Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 2009417:1–13CrossRefGoogle Scholar
  54. 54.
    Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 29:169–202PubMedCrossRefGoogle Scholar
  55. 55.
    Giulivi C, Poderoso JJ, Boveris A (1998) Production of nitric oxide by mitochondria. J Biol Chem 273:11038–11043PubMedCrossRefGoogle Scholar
  56. 56.
    Ghafourifar P, Richter C (1997) Nitric oxide synthase activity in mitochondria. FEBS Lett 418:291–296PubMedCrossRefGoogle Scholar
  57. 57.
    Sarkela TM, Berthiaume J, Elfering S et al (2001) The modulation of oxygen radical production by nitric oxide in mitochondria. J Biol Chem 276:6945–6949PubMedCrossRefGoogle Scholar
  58. 58.
    Cleeter MW, Cooper JM, Darley-Usmar VM et al (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide: implications for neurodegenerative diseases. FEBS Lett 345:50–54PubMedCrossRefGoogle Scholar
  59. 59.
    Levine RL, Stadtman ER (2001) Oxidative modification of proteins during aging. Exp Gerontol 36:1495–1502PubMedCrossRefGoogle Scholar
  60. 60.
    Urata Y, Honma S, Goto S et al (1999) Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med 27:838–847PubMedCrossRefGoogle Scholar
  61. 61.
    Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 7:444–458PubMedCrossRefGoogle Scholar
  62. 62.
    Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600PubMedCrossRefGoogle Scholar
  63. 63.
    Van Remmen H, Hamilton ML, Richardson A (2003) Oxidative damage to DNA and aging. Exerc Sport Sci Rev 31:149–153PubMedCrossRefGoogle Scholar
  64. 64.
    Stadtman ER (2002) Importance of individuality in oxidative stress and aging. Free Radic Biol Med. 33:597–604PubMedCrossRefGoogle Scholar
  65. 65.
    Van Remmen H, Richardson A (2001) Oxidative damage to mitochondria and aging. Exp Gerontol 36:957–968PubMedCrossRefGoogle Scholar
  66. 66.
    Yan LJ, Levine RL, Sohal R (1997) Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA 94:11168–11172PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777:1249–1262PubMedCrossRefGoogle Scholar
  68. 68.
    Reiter RJ, Tan DX, Galano A (2014) Melatonin: exceeding expectations. Physiology (Bethesda) 29:325–333Google Scholar
  69. 69.
    Cuzzocrea S, Zingarelli B, Gilad E et al (1997) Protective effect of melatonin in carrageenan-induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res 23:106–116PubMedCrossRefGoogle Scholar
  70. 70.
    Halladin NL, Ekeløf S, Jensen SE et al (2014) Melatonin does not affect oxidative/inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction. In Vivo 28:483–488PubMedGoogle Scholar
  71. 71.
    Mauriz JL, Collado PS, Veneroso C et al (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 54:1–14PubMedCrossRefGoogle Scholar
  72. 72.
    Antolín I, Rodríguez C, Saínz RM et al (1996) Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 10:882–890PubMedGoogle Scholar
  73. 73.
    Martín M, Macías M, Escames G et al (2000) Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J Pineal Res 28:242–248PubMedCrossRefGoogle Scholar
  74. 74.
    López A, García JA, Escames G et al (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188–198PubMedCrossRefGoogle Scholar
  75. 75.
    Reiter RJ, Tan DX, Galano A (2014) Melatonin reduces lipid peroxidation and membrane viscosity. Front Physiol 5:377–380PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pieri C, Marra M, Gaspar R et al (1996) Melatonin protects LDL from oxidation but does not prevent the apolipoprotein derivatization. Biochem Biophys Res Commun 2:256–260CrossRefGoogle Scholar
  77. 77.
    Livrea MA, Tesoriere L, D’arpa D et al (1997) Reaction of melatonin with lipoperoxyl radicals in phospholipid bilayers. Free Radic Biol Med 5:706–711CrossRefGoogle Scholar
  78. 78.
    Pieri C, Marra M, Moroni F et al (1994) Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci. 55:PL271–PL276PubMedCrossRefGoogle Scholar
  79. 79.
    Ceraulo L, Ferrugia M, Tesoriere L et al (1999) Interactions of melatonin with membrane models: portioning of melatonin in AOT and lecithin reversed micelles. J Pineal Res 26:108–112PubMedCrossRefGoogle Scholar
  80. 80.
    Teixeira A, Morfim MP, de Cordova CA et al (2003) Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite. J Pineal Res 35:262–268PubMedCrossRefGoogle Scholar
  81. 81.
    Maharaj DS, Maharaj H, Daya S et al (2006) Melatonin and 6-hydroxymelatonin protect against iron-induced neurotoxicity. J Neurochem 1:78–81CrossRefGoogle Scholar
  82. 82.
    Parlakpinar H, Sahna E, Ozer MK et al (2002) Physiological and pharmacological concentrations of melatonin protect against cisplatin-induced acute renal injury. J Pineal Res 33:161–166PubMedCrossRefGoogle Scholar
  83. 83.
    Reiter RJ, Tan D, Kim SJ et al (1999) Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Ageing Dev 110:157–173PubMedCrossRefGoogle Scholar
  84. 84.
    Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. J Pineal Res 55:325–356PubMedGoogle Scholar
  85. 85.
    Tan DX, Manchester LC, Reiter RJ et al (2000) Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. Free Radic Biol Med. 29:1177–1185PubMedCrossRefGoogle Scholar
  86. 86.
    Tan DX, Manchester LC, Fuentes-Broto L et al (2011) Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 12:167–188PubMedCrossRefGoogle Scholar
  87. 87.
    Zhang M, Mileykovskaya E, Dowhan W (2002) Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane. J Biol Chem 277:43553–43556PubMedCrossRefGoogle Scholar
  88. 88.
    Schlame M, Ren M (2009) The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim Biophys Acta 1788:2080–2083PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Klingenberg M (2009) Cardiolipin and mitochondrial carriers. Biochim Biophys Acta 1788:2048–2058PubMedCrossRefGoogle Scholar
  90. 90.
    Schagger H (2002) Respiratory chain supercomplexes of mitochondria and bacteria. Biochim Biophys Acta 1555:154–159PubMedCrossRefGoogle Scholar
  91. 91.
    Duncan AL, Robinson AJ, Walker JE (2016) Cardiolipin binds selectively but transiently to conserved lysine residues in the rotor of metazoan ATP synthases. Proc Natl Acad Sci USA 113:8687–8692PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Gonzalvez F, Gottlieb E (2007) Cardiolipin: setting the beat of apoptosis. Apoptosis 12:877–885PubMedCrossRefGoogle Scholar
  93. 93.
    Ott M, Zhivotovsky B, Orrenius S (2007) Role of cardiolipin in cytochrome c release from mitochondria. Cell Death Differ 14:1243–1247PubMedCrossRefGoogle Scholar
  94. 94.
    Petrosillo G, Casanova G, Matera M et al (2006) Interaction of peroxidized cardiolipin with rat-heart mitochondrial membranes: induction of permeability transition and cytochrome c release. FEBS Lett 580:6311–6316PubMedCrossRefGoogle Scholar
  95. 95.
    Ban T, Heymann JA, Song Z et al (2010) OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet 19:2113–2122PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Marom M, Safonov R, Amram S et al (2009) Interaction of the Tim44 C-terminal domain with negatively charged phospholipids. Biochemistry 48:11185–11195PubMedCrossRefGoogle Scholar
  97. 97.
    Xiao M, Zhong H, Xia L et al (2017) Pathophysiology of mitochondrial lipid oxidation: role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria. Free Radic Biol Med. doi: 10.1016/j.freeradbiomed.2017.04.363 Google Scholar
  98. 98.
    Hsu P, Shi Y (2017) Regulation of autophagy by mitochondrial phospholipids in health and diseases. Biochim Biophys Acta 1862:114–129PubMedCrossRefGoogle Scholar
  99. 99.
    Catalá A (2007) The ability of melatonin to counteract lipid peroxidation in biological membranes. Curr Mol Med 7:638–649PubMedCrossRefGoogle Scholar
  100. 100.
    Petrosillo G, Di Venosa N, Pistolese M et al (2006) Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia–reperfusion: role of cardiolipin. FASEB J 20:269–276PubMedCrossRefGoogle Scholar
  101. 101.
    Mekhloufi J, Bonnefont-Rousselot D et al (2005) Antioxidant activity of melatonin and apinoline derivative on linoleate model system. J Pineal Res 39:27–33PubMedCrossRefGoogle Scholar
  102. 102.
    Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292:C670–C686PubMedCrossRefGoogle Scholar
  103. 103.
    Petrosillo G, De Benedictis V, Ruggiero FM et al (2013) Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin. J Bioenerg Biomembr 45:431–440PubMedCrossRefGoogle Scholar
  104. 104.
    Paradies G, Petrosillo G, Paradies V et al (2010) Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med 48:1286–1295PubMedCrossRefGoogle Scholar
  105. 105.
    Lenaz G, Bovina C, Castelluccio C et al (1997) Mitochondrial complex I defects in aging. Mol Cell Biochem 174:329–333PubMedCrossRefGoogle Scholar
  106. 106.
    Petrosillo G, Matera M, Casanova G et al (2008) Mitochondrial dysfunction in rat brain with aging Involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int 53:126–131PubMedCrossRefGoogle Scholar
  107. 107.
    Petrosillo G, Matera M, Moro et al (2009) Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med 46:88–94PubMedCrossRefGoogle Scholar
  108. 108.
    Lange C, Nett JH, Trumpower BL et al (2001) Specific roles of protein-phospholipid interactions in the yeast cytochrome bc1 complex structure. EMBO J, pp 206591–206600Google Scholar
  109. 109.
    Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2011) Mitochondrial dysfunction in brain aging: role of oxidative stress and cardiolipin. Neurochem Int 58:447–457PubMedCrossRefGoogle Scholar
  110. 110.
    Genova ML, Lenaz G (2014) Functional role of mitochondrial respiratory supercomplexes. Biochim Biophys Acta 1837:427–443PubMedCrossRefGoogle Scholar
  111. 111.
    Bazán S, Mileykovskaya E, Mallampalli VK et al (2013) Cardiolipin-dependent reconstitution of respiratory supercomplexes from purified Saccharomyces cerevisiae complexes III and IV. J Biol Chem 288:401–411PubMedCrossRefGoogle Scholar
  112. 112.
    McKenzie M, Lazarou M, Thorburn DR et al (2006) Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol 361:462–469PubMedCrossRefGoogle Scholar
  113. 113.
    Gómez LA, Hagen TM (2012) Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? Semin Cell Dev Biol 23:758–767PubMedCrossRefGoogle Scholar
  114. 114.
    Carretero M, Escames G, López LC et al (2009) Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res 47:192–200PubMedCrossRefGoogle Scholar
  115. 115.
    Caballero B, Vega-Naredo I, Sierra V, Huidobro-Fernández C, Soria-Valles C, De Gonzalo-Calvo D, Tolivia D, Gutierrez-Cuesta J, Pallas M, Camins A, Rodríguez-Colunga MJ, Coto-Montes A (2008) Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence-accelerated mice. J Pineal Res 45:302–311PubMedCrossRefGoogle Scholar
  116. 116.
    Schapira AH, Cooper JM, Dexter D et al (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54:823–827PubMedCrossRefGoogle Scholar
  117. 117.
    Schon EA, Manfredi G (2003) Neuronal degeneration and mitochondrial dysfunction. J. Clin. Invest. 111:303–312PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Perier C, Tieu K, Guégan C et al (2005) Complex I deficiency primes Bax dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci USA 102:19126–19131PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–952PubMedCrossRefGoogle Scholar
  121. 121.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedCrossRefGoogle Scholar
  122. 122.
    Halestrap AP, Davidson AM (1990) Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J. 268:153–160PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Novgorodov SA, Gudz TI, Jung DW et al (1991) The nonspecific inner membrane pore of liver mitochondria: modulation of cyclosporin sensitivity by ADP at carboxyatractyloside-sensitive and insensitive sites. Biochem Biophys Res Commun 180:33–38PubMedCrossRefGoogle Scholar
  124. 124.
    Kokoszka JE, Waymire KG, Levy SE et al (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Basso E, Petronilli V, Forte MA et al (2008) Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. J Biol Chem 283:26307–26311PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Gerle C (2016) On the structural possibility of pore-forming mitochondrial FoF1 ATP synthase. Biochim Biophys Acta 1857:1191–1196PubMedCrossRefGoogle Scholar
  127. 127.
    Giorgio V, Bisetto E, Soriano ME et al (2009) Cyclophilin D modulates mitochondrial FoF1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Richardson AP, Halestrap AP (2016) Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity. Biochem J 473:1129–1140PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Halestrap AP (2014) The C ring of the F1Fo ATP synthase forms the mitochondrial permeability transition pore: a critical appraisal. Front Oncol 4:234PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Chen C, Ko Y, Delannoy M et al (2004) Mitochondrial ATP synthasome: three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J Biol Chem 279:31761–31768PubMedCrossRefGoogle Scholar
  133. 133.
    Biasutto L, Azzolini M, Szabò I et al (2016) The mitochondrial permeability transition pore in AD 2016: an update. Biochim Biophys Acta 1863:2515–2530PubMedCrossRefGoogle Scholar
  134. 134.
    Bernardi P, Di Lisa F (2015) The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 78:100–106PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Claypool SM, Oktay Y, Boontheung P et al (2008) Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane. J Cell Biol 182:937–950PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Laage S, Tao Y, McDermott AE (2015) Cardiolipin interaction with subunit c of ATP synthase: solid-state NMR characterization. Biochim Biophys Acta 1848:260–265PubMedCrossRefGoogle Scholar
  137. 137.
    Li B, Chauvin C, De Paulis D et al (2012) Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D. Biochim Biophys Acta 1817:1628–1634PubMedCrossRefGoogle Scholar
  138. 138.
    Grimm S, Brdiczka D (2007) The permeability transition pore in cell death. Apoptosis 12:841–855PubMedCrossRefGoogle Scholar
  139. 139.
    Rytömaa M, Mustonen P, Kinnunen PK (1992) Reversible, nonionic, and pH dependent association of cytochrome c with cardiolipin–phosphatidylcholine liposomes. J Biol Chem 267:22243–22248PubMedGoogle Scholar
  140. 140.
    Petrosillo G, Ruggiero FM, Paradies G (2003) Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FASEB J 15:2202–2208CrossRefGoogle Scholar
  141. 141.
    Hibaoui Y, Roulet E, Ruegg UT (2009) Melatonin prevents oxidative stress-mediated mitochondrial permeability transition and death in skeletal muscle cells. J Pineal Res 47:238–252PubMedCrossRefGoogle Scholar
  142. 142.
    Camara AK, Bienengraeber M, Stowe DF (2011) Mitochondrial approaches to protect against cardiac ischemia and reperfusion injury. Front Physiol 2:1–34CrossRefGoogle Scholar
  143. 143.
    Ong SB, Samangouei P, Kalkhoran SB et al (2015) The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J Mol Cell Cardiol 78:23–34PubMedCrossRefGoogle Scholar
  144. 144.
    Paradies G, Paradies V, Ruggiero FM et al (2015) Cardiolipin alterations and mitochondrial dysfunction in heart ischemia/reperfusion injury. Clin. Lipidol. 10:415–429CrossRefGoogle Scholar
  145. 145.
    Petrosillo G, Colantuono G, Moro N et al (2009) Melatonin protects against heart ischemia–reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol 297:H1487–H1493PubMedCrossRefGoogle Scholar
  146. 146.
    Paradies G, Paradies V, Ruggiero et al (2013) Changes in the mitochondrial permeability transition pore in aging and age-associated diseases. Mech Ageing Dev 134:1–9PubMedCrossRefGoogle Scholar
  147. 147.
    Mather M, Rottenberg H (2000) Aging enhances the activation of the permeability transition pore in mitochondria. Biochem Biophys Res Commun 273:603–608PubMedCrossRefGoogle Scholar
  148. 148.
    Petrosillo G, Moro N, Paradies V et al (2010) Increased susceptibility to Ca(2+)-induced permeability transition and to cytochrome c release in rat heart mitochondria with aging: effect of melatonin. J Pineal Res 48:340–346PubMedCrossRefGoogle Scholar
  149. 149.
    Kajstura J, Cheng W, Sarangarajan R (1996) Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol 271:H1215–H1228PubMedGoogle Scholar
  150. 150.
    Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505PubMedCrossRefGoogle Scholar
  151. 151.
    Mullin S, Schapira AH (2015) Pathogenic mechanisms of neurodegeneration in Parkinson disease. Neurol Clin 33:1–17PubMedCrossRefGoogle Scholar
  152. 152.
    Protter D, Lang C, Cooper AA (2012) αSynuclein and mitochondrial dysfunction: a pathogenic partnership in Parkinson’s disease? Parkinsons Dis 2012:829207PubMedPubMedCentralGoogle Scholar
  153. 153.
    Pranke IM, Morello V, Bigay J (2011) α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding. J Cell Biol 194:89–103PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Büeler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 218:235–246PubMedCrossRefGoogle Scholar
  155. 155.
    Ikon N, Ryan RO (2017) Cardiolipin and mitochondrial cristae organization. Biochim Biophys Acta 1859:1156–1163PubMedCrossRefGoogle Scholar
  156. 156.
    Ghio S, Kamp F, Cauchi R et al (2016) Interaction of α-synuclein with biomembranes in Parkinson’s disease—role of cardiolipin. Prog Lipid Res 61:73–82PubMedCrossRefGoogle Scholar
  157. 157.
    Ellis CE, Murphy EJ, Mitchell DC et al (2005) Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol 25:10190–10201PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Bayir H, Kapralov AA, Jiang J, Huang Z, Tyurina YY, Tyurin VA, Zhao Q, Belikova NA, Vlasova II, Maeda A, Zhu J, Na HM, Mastroberardino PG, Sparvero LJ, Amoscato AA, Chu CT, Greenamyre JT, Kagan VE (2009) Peroxidase mechanism of lipid-dependent cross-linking of synuclein with cytochrome c: protection against apoptosis versus delayed oxidative stress in Parkinson disease. J Biol Chem 284:15951–15969PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Ganie SA, Dar TA, Bhat AH et al (2016) Melatonin: a potential anti-oxidant therapeutic agent for mitochondrial dysfunctions and related disorders. Rejuvenation Res 19:21–40PubMedCrossRefGoogle Scholar
  160. 160.
    Saravanan KS, Sindhu KM, Mohanakumar KP (2007) Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res 42:247–253PubMedCrossRefGoogle Scholar
  161. 161.
    Patki G, Lau YS (2011) Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson’s disease. Pharmacol Biochem Behav 99:704–711PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Ortiz GG, Crespo-López ME, Morán-Moguel C et al (2001) Protective role of melatonin against MPTP-induced mouse brain cell DNA fragmentation and apoptosis in vivo. Neuro Endocrinol Lett 22:101–108PubMedGoogle Scholar
  163. 163.
    Srinivasan V, Cardinali DP, Srinivasan US (2011) Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection. Ther Adv Neurol Disord 4:297–317PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Bir A, Sen O, Anand S (2014) α-Synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: implications in the pathogenesis of Parkinson’s disease. J Neurochem 131:868–877PubMedCrossRefGoogle Scholar
  165. 165.
    Martin LJ, Semenkow S, Hanaford A et al (2014) Mitochondrial permeability transition pore regulates Parkinson’s disease development in mutant α-synuclein transgenic mice. Neurobiol Aging 35:1132–1152PubMedCrossRefGoogle Scholar
  166. 166.
    Ehrnhoefer DE, Wong BK, Hayden MR (2011) Convergent pathogenic pathways in Alzheimer’s and Huntington’s diseases: shared targets for drug development. Nat Rev Drug Discov 10:853–867PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Santos RX, Correia SC, Wang X et al (2010) Alzheimer’s disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol 3:570–581PubMedPubMedCentralGoogle Scholar
  168. 168.
    Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem. doi: 10.1111/jnc.14037 Google Scholar
  169. 169.
    Chen JX, Yan SS (2010) Role of mitochondrial amyloid-beta in Alzheimer’s disease. J Alzheimers Dis 20(Suppl 2):S569–S578PubMedCrossRefGoogle Scholar
  170. 170.
    Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Dong W, Huang F, Fan W et al (2010) Differential effects of melatonin on amyloid-beta peptide 25–35-induced mitochondrial dysfunction in hippocampal neurons at different stages of culture. J Pineal Res 48:117–125PubMedCrossRefGoogle Scholar
  172. 172.
    Wang X (2009) The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther 15:345–357PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Feng Z, Qin C, Chang Y et al (2006) Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic Biol Med 40:101–109PubMedCrossRefGoogle Scholar
  174. 174.
    Gauba E, Guo L, Du H (2017) Cyclophilin D promotes brain mitochondrial F1FO ATP synthase dysfunction in aging mice. J Alzheimers Dis 55:1351–1362PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Jou MJ, Peng TI, Reiter RJ et al (2004) Visualization of the antioxidative effects of melatonin at the mitochondrial level during oxidative stress-induced apoptosis of rat brain astrocytes. J Pineal Res 37:55–70PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Giuseppe Paradies
    • 1
  • Valeria Paradies
    • 1
  • Francesca M. Ruggiero
    • 1
  • Giuseppe Petrosillo
    • 2
  1. 1.Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
  2. 2.Institute of Biomembranes, Bioenergetics and Molecular BiotechnologiesNational Research CouncilBariItaly

Personalised recommendations