Cellular and Molecular Life Sciences

, Volume 74, Issue 21, pp 3883–3896 | Cite as

Melatonin and the electron transport chain

  • Rüdiger Hardeland
Multi-author review


Melatonin protects the electron transport chain (ETC) in multiple ways. It reduces levels of ·NO by downregulating inducible and inhibiting neuronal nitric oxide synthases (iNOS, nNOS), thereby preventing excessive levels of peroxynitrite. Both ·NO and peroxynitrite-derived free radicals, such as ·NO2, hydroxyl (·OH) and carbonate radicals (CO3·) cause blockades or bottlenecks in the ETC, by ·NO binding to irons, protein nitrosation, nitration and oxidation, changes that lead to electron overflow or even backflow and, thus, increased formation of superoxide anions (O2·). Melatonin improves the intramitochondrial antioxidative defense by enhancing reduced glutathione levels and inducing glutathione peroxidase and Mn-superoxide dismutase (Mn-SOD) in the matrix and Cu,Zn-SOD in the intermembrane space. An additional action concerns the inhibition of cardiolipin peroxidation. This oxidative change in the membrane does not only initiate apoptosis or mitophagy, as usually considered, but also seems to occur at low rate, e.g., in aging, and impairs the structural integrity of Complexes III and IV. Moreover, elevated levels of melatonin inhibit the opening of the mitochondrial permeability transition pore and shorten its duration. Additionally, high-affinity binding sites in mitochondria have been described. The assumption of direct binding to the amphipathic ramp of Complex I would require further substantiation. The mitochondrial presence of the melatonin receptor MT1 offers the possibility that melatonin acts via an inhibitory G protein, soluble adenylyl cyclase, decreased cAMP and lowered protein kinase A activity, a signaling pathway shown to reduce Complex I activity in the case of a mitochondrial cannabinoid receptor.


Electron leakage Melatonin NADPH oxidase Reactive nitrogen species Reactive oxygen species 


  1. 1.
    Lane MN (2006) Mitochondrial disease: powerhouse of disease. Nature 440:600–602PubMedCrossRefGoogle Scholar
  2. 2.
    Messner M, Hardeland R, Rodenbeck A, Huether G (1998) Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions. J Pineal Res 25:251–259PubMedCrossRefGoogle Scholar
  3. 3.
    López A, García JA, Escames G, Venegas C, Ortíz F, López LC, Acuña-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188–198PubMedCrossRefGoogle Scholar
  4. 4.
    Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48:297–310PubMedCrossRefGoogle Scholar
  5. 5.
    Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C, García-Corzo L, López LC, Reiter RJ, Acuña-Castroviejo D (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227PubMedCrossRefGoogle Scholar
  6. 6.
    Hardeland R (2012) Melatonin in aging and disease—multiple consequences of reduced secretion, options and limits of treatment. Aging Dis 3:194–225PubMedGoogle Scholar
  7. 7.
    Hardeland R (2012) Neurobiology, pathophysiology, and treatment of melatonin deficiency and dysfunction. ScientificWorldJournal 2012:640389. doi: 10.1100/2012/640389 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Choksi KB, Boylston WH, Rabek JP, Widger WR, Papaconstantinou J (2004) Oxidatively damaged proteins of heart mitochondrial electron transport complexes. Biochim Biophys Acta 1688:95–101PubMedCrossRefGoogle Scholar
  9. 9.
    Miwa S, Brand MD (2005) The topology of superoxide production by complex III and glycerol 3-phosphate dehydrogenase in Drosophila mitochondria. Biochim Biophys Acta 1709:214–219PubMedCrossRefGoogle Scholar
  10. 10.
    Panee J, Liu W, Nakamura K, Berry MJ (2007) The responses of HT22 cells to the blockade of mitochondrial complexes and potential protective effect of selenium supplementation. Int J Biol Sci 3:335–341PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hardeland R, Poeggeler B, Pappolla MA (2009) Mitochondrial actions of melatonin—an endeavor to identify their adaptive and cytoprotective mechanisms. Proc Saxon Acad Sci 65(Pt 3):14–31Google Scholar
  12. 12.
    Staniek K, Gille L, Kozlov AV, Nohl H (2002) Mitochondrial superoxide radical formation is controlled by electron bifurcation to the high and low potential pathways. Free Radic Res 36:381–387PubMedCrossRefGoogle Scholar
  13. 13.
    Gong X, Yu L, Xia D, Yu CA (2005) Evidence for electron equilibrium between the two hemes bL in the dimeric cytochrome bc1 complex. J Biol Chem 280:9251–9257PubMedCrossRefGoogle Scholar
  14. 14.
    Iñarrea P, Casanova A, Alava MA, Iturralde M, Cadenas E (2011) Melatonin and steroid hormones activate Cu, Zn-superoxide dismutase by means of mitochondrial cytochrome P450. Free Radic Biol Med 50:1575–1581PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    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
  16. 16.
    Genova ML, Ventura B, Giuliano G, Bovina C, Formiggini G, Parenti Castelli G, Lenaz G (2001) The site of production of superoxide radical in mitochondrial Complex I is not a bound ubisemiquinone but presumably iron-sulfur cluster N2. FEBS Lett 505:364–368PubMedCrossRefGoogle Scholar
  17. 17.
    Lenaz G, Bovina C, D’Aurelio M, Fato R, Formiggini G, Genova ML, Giuliano G, Merlo Pich M, Paolucci U, Parenti Castelli G, Ventura B (2002) Role of mitochondria in oxidative stress and aging. Ann NY Acad Sci 959:199–213PubMedCrossRefGoogle Scholar
  18. 18.
    Genova ML, Merlo Pich M, Bernacchia A, Bianchi C, Biondi A, Bovina C, Falasca AI, Formiggini G, Parenti Castelli G, Lenaz G (2004) The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann NY Acad Sci 1011:86–100PubMedCrossRefGoogle Scholar
  19. 19.
    Ohnishi ST, Ohnishi T, Muranaka S, Fujita H, Kimura H, Uemura K, Yoshida K, Utsumi K (2005) A possible site of superoxide generation in the complex I segment of rat heart mitochondria. J Bioenerg Biomembr 37:1–15PubMedCrossRefGoogle Scholar
  20. 20.
    Lenaz G, Fato R, Genova ML, Bergamini C, Bianchi C, Biondi A (2006) Mitochondrial complex I: structural and functional aspects. Biochim Biophys Acta 1757:1406–1420PubMedCrossRefGoogle Scholar
  21. 21.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedCrossRefGoogle Scholar
  22. 22.
    Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, Brann DW (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12:7. doi: 10.1186/s13024-017-0150-7 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Block K, Gorin Y, Abboud HE (2009) Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci USA 106:14385–14390PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kozieł R, Pircher H, Kratochwil M, Lener B, Hermann M, Dencher NA, Jansen-Dürr P (2013) Mitochondrial respiratory chain complex I is inactivated by NADPH oxidase Nox4. Biochem J 452:231–239PubMedCrossRefGoogle Scholar
  25. 25.
    Wolin MS (2013) Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence. Biochem J 452:e1–e2PubMedCrossRefGoogle Scholar
  26. 26.
    Hirschhäuser C, Bornbaum J, Reis A, Böhme S, Kaludercic N, Menabò R, Di Lisa F, Boengler K, Shah AM, Schulz R, Schmidt HH (2015) NOX4 in mitochondria: yeast two-hybrid-based interaction with complex I without relevance for basal reactive oxygen species? Antioxid Redox Signal 23:1106–1112PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Asensio-López MC, Soler F, Sánchez-Más J, Pascual-Figal D, Fernández-Belda F, Lax A (2016) Early oxidative damage induced by doxorubicin: source of production, protection by GKT137831 and effect on Ca2+ transporters in HL-1 cardiomyocytes. Arch Biochem Biophys 594:26–36PubMedCrossRefGoogle Scholar
  28. 28.
    Forred BJ, Daugaard DR, Titus BK, Wood RR, Floen MJ, Booze ML, Vitiello PF (2017) Detoxification of mitochondrial oxidants and apoptotic signaling are facilitated by thioredoxin-2 and peroxiredoxin-3 during hyperoxic injury. PLoS One 12:e0168777. doi: 10.1371/journal.pone.0168777 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Huang Q, Zhou HJ, Zhang H, Huang Y, Hinojosa-Kirschenbaum F, Fan P, Yao L, Belardinelli L, Tellides G, Giordano FJ, Budas GR, Min W (2015) Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function. Circulation 131:1082–1897PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Pober JS, Min W, Bradley JR (2009) Mechanisms of endothelial dysfunction, injury, and death. Annu Rev Pathol 4:71–95PubMedCrossRefGoogle Scholar
  31. 31.
    Hardeland R (2009) Melatonin, mitochondrial electron flux and leakage: recent findings and resolution of contradictory results. Adv Stud Biol 1:207–230Google Scholar
  32. 32.
    Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR (2015) Melatonin and brain inflammaging. Prog Neurobiol 127–128:46–63PubMedCrossRefGoogle Scholar
  33. 33.
    Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355PubMedCrossRefGoogle Scholar
  34. 34.
    Dahm CC, Moore K, Murphy MP (2006) Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite: implications for the interaction of nitric oxide with mitochondria. J Biol Chem 281:10056–10065PubMedCrossRefGoogle Scholar
  35. 35.
    Hardeland R (2009) Neuroprotection by radical avoidance: search for suitable agents. Molecules 14:5054–5102PubMedCrossRefGoogle Scholar
  36. 36.
    Hardeland R, Coto-Montes A (2010) New vistas on oxidative damage and aging. Open Biol J 3:39–52CrossRefGoogle Scholar
  37. 37.
    Guenther AL, Schmidt SI, Laatsch H, Fotso S, Ness H, Ressmeyer A-R, Poeggeler B, Hardeland R (2005) Reactions of the melatonin metabolite AMK (N 1-acetyl-5-methoxykynuramine) with reactive nitrogen species: formation of novel compounds, 3-acetamidomethyl-6-methoxycinnolinone and 3-nitro-AMK. J Pineal Res 39:251–260PubMedCrossRefGoogle Scholar
  38. 38.
    Klingen AR, Palsdottir H, Hunte C, Ullmann GM (2007) Redox-linked protonation state changes in cytochrome bc1 identified by Poisson-Boltzmann electrostatics calculations. Biochim Biophys Acta 1767:204–221PubMedCrossRefGoogle Scholar
  39. 39.
    Lesnefsky EJ, Hoppel CL (2008) Cardiolipin as an oxidative target in cardiac mitochondria in the aged rat. Biochim Biophys Acta 1777:1020–1027PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Lesnefsky EJ, Minkler P, Hoppel CL (2009) Enhanced modification of cardiolipin during ischemia in the aged heart. J Mol Cell Cardiol 46:1008–1015PubMedCrossRefGoogle Scholar
  41. 41.
    Wenz T, Hielscher R, Hellwig P, Schägger H, Richers S, Hunte C (2009) Role of phospholipids in respiratory cytochrome bc1 complex catalysis and supercomplex formation. Biochim Biophys Acta 1787:609–616PubMedCrossRefGoogle Scholar
  42. 42.
    Basova LV, Kurnikov IV, Wang L, Ritov VB, Belikova NA, Vlasova II, Pacheco AA, Winnica DE, Peterson J, Bayir H, Waldeck DH, Kagan VE (2007) Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activity. Biochemistry 46:3423–3434PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kagan VE, Bayir A, Bayir H, Stoyanovsky D, Borisenko GG, Tyurina YY, Wipf P, Atkinson J, Greenberger JS, Chapkin RS, Belikova NA (2009) Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: a new strategy in anti-apoptotic drug discovery. Mol Nutr Food Res 53:104–114PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovski 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 46:1439–1453PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zoccarato F, Cavallini L, Alexandre A (2009) Succinate is the controller of O2 /H2O2 release at mitochondrial complex I: negative modulation by malate, positive by cyanide. J Bioenerg Biomembr 41:387–393PubMedCrossRefGoogle Scholar
  46. 46.
    Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L, Grishin NV, White M, Yang XJ, Zhao Y (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23:607–618PubMedCrossRefGoogle Scholar
  47. 47.
    Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382:790–801PubMedCrossRefGoogle Scholar
  48. 48.
    López LC, Escames G, Tapias V, Utrilla P, León J, Acuña-Castroviejo D (2006) Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice: its relation with mitochondrial dysfunction and prevention by melatonin. Int J Biochem Cell Biol 38:267–278PubMedCrossRefGoogle Scholar
  49. 49.
    Escames G, López LC, Ortíz F, López A, García JA, Ros E, Acuña-Castroviejo D (2007) Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J 274:2135–2147PubMedCrossRefGoogle Scholar
  50. 50.
    Tapias V, Escames G, López LC, López A, Camacho E, Carrión MD, Entrena A, Gallo MA, Espinosa A, Acuña-Castroviejo D (2009) Melatonin and its brain metabolite N 1-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice. J Neurosci Res 87:3002–3010PubMedCrossRefGoogle Scholar
  51. 51.
    Ortiz F, García JA, Acuña-Castroviejo D, Doerrier C, López A, Venegas C, Volt H, Luna-Sánchez M, López LC, Escames G (2014) The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS. J Pineal Res 56:71–81PubMedCrossRefGoogle Scholar
  52. 52.
    García JA, Ortiz F, Miana J, Doerrier C, Fernández-Ortiz M, Rusanova I, Escames G, García JJ, Acuña-Castroviejo D (2017) Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice. J Physiol Biochem. doi: 10.1007/s13105-017-0548-2 [Epub ahead of print, Jan 21] PubMedGoogle Scholar
  53. 53.
    León J, Vives F, Crespo E, Camacho E, Espinosa A, Gallo MA, Escames G, Acuña-Castroviejo D (1998) Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. J Neuroendocrinol 10:297–302PubMedCrossRefGoogle Scholar
  54. 54.
    León J, Macías M, Escames G, Camacho E, Khaldy H, Martín M, Espinosa A, Gallo MA, Acuña-Castroviejo D (2000) Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines. Mol Pharmacol 58:967–975PubMedGoogle Scholar
  55. 55.
    Chang HM, Ling EA, Chen CF, Lue H, Wen CY, Shieh JY (2002) Melatonin attenuates the neuronal NADPH-d/NOS expression in the nodose ganglion of acute hypoxic rats. J Pineal Res 32:65–73PubMedCrossRefGoogle Scholar
  56. 56.
    Acuña-Castroviejo D, Escames G, López LC, Hitos AB, León J (2005) Melatonin and nitric oxide: two required antagonists for mitochondrial homeostasis. Endocrine 27:159–168PubMedCrossRefGoogle Scholar
  57. 57.
    Entrena A, Camacho ME, Carrión MD, López-Cara LC, Velasco G, León J, Escames G, Acuña-Castroviejo D, Tapias V, Gallo MA, Vivo A, Espinosa A (2005) Kynurenamines as neural nitric oxide synthase inhibitors. J Med Chem 48:8174–8181PubMedCrossRefGoogle Scholar
  58. 58.
    Jiménez-Ortega V, Cano P, Cardinali DP, Esquifino AI (2009) 24-Hour variation in gene expression of redox pathway enzymes in rat hypothalamus: effect of melatonin treatment. Redox Rep 14:132–138PubMedCrossRefGoogle Scholar
  59. 59.
    Tjong YW, Li MF, Hung MW, Fung ML (2008) Melatonin ameliorates hippocampal nitric oxide production and large conductance calcium-activated potassium channel activity in chronic intermittent hypoxia. J Pineal Res 44:234–243PubMedCrossRefGoogle Scholar
  60. 60.
    Escames G, Acuña-Castroviejo D, López LC, Tan D-X, Maldonado MD, Sánchez-Hidalgo M, León J, Reiter RJ (2006) Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. J Pharm Pharmacol 58:1153–1165PubMedCrossRefGoogle Scholar
  61. 61.
    López LC, Escames G, Ortíz F, Ros E, Acuña-Castroviejo D (2006) Melatonin restores the mitochondrial production of ATP in septic mice. Neuroendocrinol Lett 27:623–630PubMedGoogle Scholar
  62. 62.
    Escames G, López LC, Ortíz F, Ros E, Acuña-Castroviejo D (2006) Age-dependent lipopolysaccharide-induced iNOS expression and multiorgan failure in rats: effects of melatonin treatment. Exp Gerontol 41:1165–1173PubMedCrossRefGoogle Scholar
  63. 63.
    Escames G, López LC, Tapias V, Utrilla P, Reiter RJ, Hitos AB, León J, Rodríguez MI, Acuña-Castroviejo D (2006) Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res 40:71–78PubMedCrossRefGoogle Scholar
  64. 64.
    Deng WG, Tang ST, Tseng HP, Wu KK (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518–524PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Korkmaz A, Rosales-Corral S, Reiter RJ (2012) Gene regulation by melatonin linked to epigenetic phenomena. Gene 503:1–11PubMedCrossRefGoogle Scholar
  66. 66.
    Tocharus J, Chongthammakun S, Govitrapong P (2008) Melatonin inhibits amphetamine-induced nitric oxide synthase mRNA overexpression in microglial cell lines. Neurosci Lett 439:134–137PubMedCrossRefGoogle Scholar
  67. 67.
    Tocharus J, Khonthun C, Chongthammakun S, Govitrapong P (2010) Melatonin attenuates methamphetamine-induced overexpression of pro-inflammatory cytokines in microglial cell lines. J Pineal Res 48:347–352PubMedCrossRefGoogle Scholar
  68. 68.
    Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin—a pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93:350–384PubMedCrossRefGoogle Scholar
  69. 69.
    Campbell A, Sharman E, Bondy SC (2014) Age-related differences in the response of the brain to dietary melatonin. Age (Dordr) 36:49–55CrossRefGoogle Scholar
  70. 70.
    Hardeland R (2016) Deacceleration of brain aging by melatonin. In: Bondy SC, Campbell A (eds) Inflammation, aging, and oxidative stress. Humana Press, New York, pp 345–376CrossRefGoogle Scholar
  71. 71.
    Srinivasan V, Pandi-Perumal SR, Spence DW, Kato H, Cardinali DP (2010) Melatonin in septic shock: some recent concepts. J Crit Care 25:656.e1–656.e6CrossRefGoogle Scholar
  72. 72.
    Farinelli SE, Park DS, Greene LA (1996) Nitric oxide delays the death of trophic factor-deprived PC12 cells and sympathetic neurons by a cGMP-mediated mechanism. J Neurosci 16:2325–2334PubMedGoogle Scholar
  73. 73.
    Estévez AG, Spear N, Thompson JA, Cornwell TL, Radi R, Barbeito L, Beckman JS (1998) Nitric oxide-dependent production of cGMP supports the survival of rat embryonic motor neurons cultured with brain-derived neurotrophic factor. J Neurosci 18:3708–3714PubMedGoogle Scholar
  74. 74.
    Robb SJ, Connor JR (2002) Nitric oxide protects astrocytes from oxidative stress. Ann NY Acad Sci 962:93–102PubMedCrossRefGoogle Scholar
  75. 75.
    Tan D-X, Chen L-D, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:57–60Google Scholar
  76. 76.
    Tan D-X, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST, Vijayalaxmi Shepherd AM (1998) A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 253:614–620PubMedCrossRefGoogle Scholar
  77. 77.
    Tan D-X, Hardeland R, Manchester LC, Galano A, Reiter RJ (2014) Cyclic-3-hydroxymelatonin (C3HOM), a potent antioxidant, scavenges free radicals and suppresses oxidative reactions. Curr Med Chem 21:1557–1565PubMedCrossRefGoogle Scholar
  78. 78.
    Tan D-X, Manchester LC, Burkhardt S, Sainz RM, Mayo JC, Kohen R, Shohami E, Huo Y-S, Hardeland R, Reiter RJ (2001) N 1-Acetyl-N 2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant. FASEB J 15:2294–2296PubMedGoogle Scholar
  79. 79.
    Ressmeyer A-R, Mayo JC, Zelosko V, Sáinz RM, Tan D-X, Poeggeler B, Antolín I, Zsizsik BK, Reiter RJ, Hardeland R (2003) Antioxidant properties of the melatonin metabolite N 1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox Rep 8:205–213PubMedCrossRefGoogle Scholar
  80. 80.
    Hardeland R, Tan D-X, Reiter RJ (2009) Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res 47:109–126PubMedCrossRefGoogle Scholar
  81. 81.
    Rosen J, Than NN, Koch D, Poeggeler B, Laatsch H, Hardeland R (2006) Interactions of melatonin and its metabolites with the ABTS cation radical: extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. J Pineal Res 41:374–381PubMedCrossRefGoogle Scholar
  82. 82.
    Semak I, Naumova M, Korik E, Terekhovich V, Wortsman J, Slominski A (2005) A novel metabolic pathway of melatonin: oxidation by cytochrome C. Biochemistry 44:9300–9307PubMedCrossRefGoogle Scholar
  83. 83.
    Hardeland R, Ressmeyer A-R, Zelosko V, Burkhardt S, Poeggeler B (2004) Metabolites of melatonin: Formation and properties of the methoxylated kynuramines AFMK and AMK. In: Haldar C, Singh SS (eds) Recent advances in endocrinology and reproduction: evolutionary, biotechnological and clinical applications. Banaras Hindu University, Varanasi, pp 21–38Google Scholar
  84. 84.
    Silva SO, Ximenes VF, Livramento JA, Catalani LH, Campa A (2005) High concentrations of the melatonin metabolite, N 1-acetyl-N 2-formyl-5-methoxykynuramine, in cerebrospinal fluid of patients with meningitis: a possible immunomodulatory mechanism. J Pineal Res 39:302–306PubMedCrossRefGoogle Scholar
  85. 85.
    León J, Escames G, Rodríguez MI, López LC, Tapias V, Entrena A, Camacho E, Carrión MD, Gallo MA, Espinosa A, Tan D-X, Reiter RJ, Acuña-Castroviejo D (2006) Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. J Neurochem 98:2023–2033PubMedCrossRefGoogle Scholar
  86. 86.
    Hardeland R, Backhaus C, Fadavi A, Hess M (2007) N 1-acetyl-5-methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: cyclization to a cinnolinone prevents formation of unstable nitrosamines. J Pineal Res 43:104–105PubMedCrossRefGoogle Scholar
  87. 87.
    Hardeland R, Backhaus C, Fadavi A (2007) Reactions of the NO redox forms NO+, ·NO and HNO (protonated NO) with the melatonin metabolite N 1-acetyl-5-methoxykynuramine (AMK). J Pineal Res 43:382–388PubMedCrossRefGoogle Scholar
  88. 88.
    Acuña-Castroviejo D, Escames G, León J, Carazo A, Khaldy H (2003) Mitochondrial regulation by melatonin and its metabolites. Adv Exp Med Biol 527:549–557PubMedCrossRefGoogle Scholar
  89. 89.
    Schaefer M, Hardeland R (2009) The melatonin metabolite N 1-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. J Pineal Res 46:49–52PubMedCrossRefGoogle Scholar
  90. 90.
    Hardeland R, Niebergall R, Schoenke M, Poeggeler B (2001) Carbonate radicals as initiators of melatonin oxidation: chemiluminescence and formation of oxidation products. In: Hardeland R (ed) Actions and redox properties of melatonin and other aromatic amino acid metabolites. Cuvillier, Göttingen, pp 49–55Google Scholar
  91. 91.
    Zelosko V, Libau K, Hardeland R (2001) Product analyses reveal rapid and preferential conversion of melatonin to AFMK under the influence of carbonate radicals. In: Hardeland R (ed) Actions and redox properties of melatonin and other aromatic amino acid metabolites. Cuvillier, Göttingen, pp 56–57Google Scholar
  92. 92.
    Hardeland R, Poeggeler B, Niebergall R, Zelosko V (2003) Oxidation of melatonin by carbonate radicals and chemiluminescence emitted during pyrrole ring cleavage. J Pineal Res 34:17–25PubMedCrossRefGoogle Scholar
  93. 93.
    Rodriguez MI, Escames G, López LC, García JA, Ortiz F, López A, Acuña-Castroviejo D (2007) Melatonin administration prevents cardiac and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice. J Endocrinol 194:637–643PubMedCrossRefGoogle Scholar
  94. 94.
    Rodríguez MI, Carretero M, Escames G, López LC, Maldonado MD, Tan DX, Reiter RJ, Acuña-Castroviejo D (2007) Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice. Free Radic Res 41:15–24PubMedCrossRefGoogle Scholar
  95. 95.
    Rodríguez MI, Escames G, López LC, López A, García JA, Ortiz F, Sánchez V, Romeu M, Acuña-Castroviejo D (2008) Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice. Exp Gerontol 43:749–756PubMedCrossRefGoogle Scholar
  96. 96.
    Jung KH, Hong SW, Zheng HM, Lee HS, Lee H, Lee DH, Lee SY, Hong SS (2010) Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J Pineal Res 48:239–250PubMedCrossRefGoogle Scholar
  97. 97.
    García-Macia M, Vega-Naredo I, De Gonzalo-Calvo D, Rodríguez-González SM, Camello PJ, Camello-Almaraz C, Martín-Cano FE, Rodríguez-Colunga MJ, Pozo MJ, Coto-Montes AM (2011) Melatonin induces neural SOD2 expression independent of the NF-kappaB pathway and improves the mitochondrial population and function in old mice. J Pineal Res 50:54–63PubMedCrossRefGoogle Scholar
  98. 98.
    Chen Y, Qing W, Sun M, Lv L, Guo D, Jiang Y (2015) Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway. Free Radic Res 49:1275–1284PubMedCrossRefGoogle Scholar
  99. 99.
    Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J, Zhang R, He M, Lu Y, Liu C, Duan W, Yu Z, Zhou Z (2015) SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11:1037–1051PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Remião MH, Lucas CG, Domingues WB, Silveira T, Barther NN, Komninou ER, Basso AC, Jornada DS, Beck RC, Pohlmann AR, Junior AS, Seixas FK, Campos VF, Guterres SS, Collares T (2016) Melatonin delivery by nanocapsules during in vitro bovine oocyte maturation decreased the reactive oxygen species of oocytes and embryos. Reprod Toxicol 63:70–81PubMedCrossRefGoogle Scholar
  101. 101.
    Song C, Peng W, Yin S, Zhao J, Fu B, Zhang J, Mao T, Wu H, Zhang Y (2016) Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Sci Rep 6:35165. doi: 10.1038/srep35165 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, Xue X, Xu Y, Meng D, Li B, Zhang M, Zhang Bin, Jin Z, Yu S, Yang Y, Wang H (2017) Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling. Sci Rep 7:41337. doi: 10.1038/srep41337 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Qiang Wang KZ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayir H, Kagan VE (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15:1197–1205PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Hsiao CW, Peng TI, Peng AC, Reiter RJ, Tanaka M, Lai YK, Jou MJ (2013) Long-term Aβ exposure augments mCa2+-independent mROS-mediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids: a protective targeting of melatonin. J Pineal Res 54:107–125PubMedCrossRefGoogle Scholar
  105. 105.
    Petrosillo G, Di Venosa N, Pistolese M, Casanova G, Tiravanti E, Colantuono G, Federici A, Paradies G, Ruggiero FM (2006) Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia-reperfusion: role of cardiolipin. FASEB J 20:269–276PubMedCrossRefGoogle Scholar
  106. 106.
    Luchetti F, Canonico B, Mannello F, Masoni C, D’Emilio A, Battistelli M, Papa S, Falcieri E (2007) Melatonin reduces early changes in intramitochondrial cardiolipin during apoptosis in U937 cell line. Toxicol In Vitro 21:293–301PubMedCrossRefGoogle Scholar
  107. 107.
    Petrosillo G, Fattoretti P, Matera M, Ruggiero FM, Bertoni-Freddari C, Paradies G (2008) Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res 11:935–943PubMedCrossRefGoogle Scholar
  108. 108.
    Petrosillo G, De Benedictis V, Ruggiero FM, Paradies G (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
  109. 109.
    Paradies G, Paradies V, Ruggiero FM, Petrosillo G (2015) Protective role of melatonin in mitochondrial dysfunction and related disorders. Arch Toxicol 89:923–939PubMedCrossRefGoogle Scholar
  110. 110.
    Liang H, Ran Q, Jang YC, Holstein D, Lechleiter J, McDonald-Marsh T, Musatov A, Song W, Van Remmen H, Richardson A (2009) Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria. Free Radic Biol Med 47:312–320PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Doerrier C, García JA, Volt H, Díaz-Casado ME, Luna-Sánchez M, Fernández-Gil B, Escames G, López LC, Acuña-Castroviejo D (2016) Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network. Mitochondrion 27:56–63PubMedCrossRefGoogle Scholar
  112. 112.
    Escames G, León J, Macías M, Khaldy H, Acuña-Castroviejo D (2003) Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 17:932–934PubMedGoogle Scholar
  113. 113.
    Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, Li J, Di S, Yue L, Liang G, Reiter RJ, Qu Y (2015) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 58:61–70PubMedCrossRefGoogle Scholar
  114. 114.
    Martín M, Macías M, Escames G, Reiter RJ, Agapito MT, Ortiz GG, Acuña-Castroviejo D (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
  115. 115.
    Martín M, Macías M, León J, Escames G, Khaldy H, Acuña-Castroviejo D (2002) Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int J Biochem Cell Biol 34:348–357PubMedCrossRefGoogle Scholar
  116. 116.
    Khaldy H, Escames G, León J, Bikjdaouene L, Acuña-Castroviejo D (2003) Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion. Neurobiol Aging 24:491–500PubMedCrossRefGoogle Scholar
  117. 117.
    Okatani Y, Wakatsuki A, Reiter RJ (2002) Melatonin protects hepatic mitochondrial respiratory chain activity in senescence-accelerated mice. J Pineal Res 32:143–148PubMedCrossRefGoogle Scholar
  118. 118.
    Okatani Y, Wakatsuki A, Reiter RJ, Miyahara Y (2002) Hepatic mitochondrial dysfunction in senescence-accelerated mice: correction by long-term, orally administered physiological levels of melatonin. J Pineal Res 33:127–133PubMedCrossRefGoogle Scholar
  119. 119.
    Okatani Y, Wakatsuki A, Reiter RJ, Miyahara Y (2003) Acutely administered melatonin restores hepatic mitochondrial physiology in old mice. Int J Biochem Cell Biol 35:367–375PubMedCrossRefGoogle Scholar
  120. 120.
    Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García L, Acuña-Castroviejo D (2009) Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res 47:192–200PubMedCrossRefGoogle Scholar
  121. 121.
    Acuña-Castroviejo D, Carretero M, Doerrier C, López LC, García-Corzo L, Tresguerres JAF, Escames G (2012) Melatonin protects lung mitochondria from aging. Age (Dordr) 34:681–692CrossRefGoogle Scholar
  122. 122.
    Wang W, Fang H, Groom L, Cheng A, Zhang W, Liu J, Wang X, Li K, Han P, Zheng M, Yin J, Wang W, Mattson MP, Kao JP, Lakatta EG, Sheu SS, Ouyang K, Chen J, Dirksen RT, Cheng H (2008) Superoxide flashes in single mitochondria. Cell 134:279–290PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Sheu SS, Wang W, Cheng H, Dirksen RT (2008) Superoxide flashes: illuminating new insights into cardiac ischemia/reperfusion injury. Future Cardiol 4:551–554PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006) Melatonin as antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta 57:573–589CrossRefGoogle Scholar
  125. 125.
    Solís-Muñoz P, Solís-Herruzo JA, Fernández-Moreira D, Gómez-Izquierdo E, García-Consuegra I, Muñoz-Yagüe T, García Ruiz I (2011) Melatonin improves mitochondrial respiratory chain activity and liver morphology in ob/ob mice. J Pineal Res 51:113–123PubMedCrossRefGoogle Scholar
  126. 126.
    Hardeland R, Poeggeler B (2008) Melatonin beyond its classical functions. Open Physiol J 1:1–23CrossRefGoogle Scholar
  127. 127.
    Huo X, Wang C, Yu Z, Peng Y, Wang S, Feng S, Zhang S, Tian X, Sun C, Liu K, Deng S, Ma X (2017) Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: an implication of the therapeutic potential. J Pineal Res. doi: 10.1111/jpi.12390 [Epub ahead of print, Jan 18] PubMedGoogle Scholar
  128. 128.
    Yuan H, Pang SF (1991) [125I]Iodomelatonin-binding sites in the pigeon brain: binding characteristics, regional distribution and diurnal variation. J Endocrinol 128:475–482PubMedCrossRefGoogle Scholar
  129. 129.
    Absi E, Ayala A, Machado A, Parrado J (2000) Protective effect of melatonin against the 1-methyl-4-phenylpyridinium-induced inhibition of complex I of the mitochondrial respiratory chain. J Pineal Res 29:40–47PubMedCrossRefGoogle Scholar
  130. 130.
    Hardeland R, Poeggeler B (2007) Actions of melatonin, its structural and functional analogs in the central nervous system and the significance of metabolism. Cent Nerv Syst Agents Med Chem 7:289–303CrossRefGoogle Scholar
  131. 131.
    Hardeland R, Poeggeler B, Pappolla MA (2008) New vistas on mitochondrial electron flux rates and aging. Cell: comment: Accessed 26 Mar 2008
  132. 132.
    Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander RM (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci 31:14496–14507PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, Pagano Zottola AC, Delamarre A, Cannich A, Vincent P, Varilh M, Robin LM, Terral G, García-Fernández MD, Colavita M, Mazier W, Drago F, Puente N, Reguero L, Elezgarai I, Dupuy JW, Cota D, Lopez-Rodriguez ML, Barreda-Gómez G, Massa F, Grandes P, Bénard G, Marsicano G (2016) A cannabinoid link between mitochondria and memory. Nature 539:555–559PubMedCrossRefGoogle Scholar
  134. 134.
    Wang Z, Liu D, Varin A, Nicolas V, Courilleau D, Mateo P, Caubere C, Rouet P, Gomez AM, Vandecasteele G, Fischmeister R, Brenner C (2016) A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death. Cell Death Dis 7:e2198. doi: 10.1038/cddis.2016.106 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Valsecchi F, Konrad C, Manfredi G (2014) Role of soluble adenylyl cyclase in mitochondria. Biochim Biophys Acta 1842:2555–2560PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ladilov Y, Appukuttan A (2014) Role of soluble adenylyl cyclase in cell death and growth. Biochim Biophys Acta 1842:2646–2655PubMedCrossRefGoogle Scholar
  137. 137.
    Lark DS, Reese LR, Ryan TE, Torres MJ, Smith CD, Lin CT, Neufer PD (2015) Protein kinase A governs oxidative phosphorylation kinetics and oxidant emitting potential at Complex I. Front Physiol 6:332. doi: 10.3389/fphys.2015.00332 PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Neviere R, Delguste F, Durand A, Inamo J, Boulanger E, Preau S (2016) Abnormal mitochondrial cAMP/PKA signaling is involved in sepsis-induced mitochondrial and myocardial dysfunction. Int J Mol Sci 17:2075. doi: 10.3390/ijms17122075 PubMedCentralCrossRefGoogle Scholar
  139. 139.
    Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF (2004) Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J 18:869–871PubMedGoogle Scholar
  140. 140.
    Jou MJ (2011) Melatonin preserves the transient mitochondrial permeability transition for protection during mitochondrial Ca2+ stress in astrocyte. J Pineal Res 50:427–435PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Johann Friedrich Blumenbach, Institute of Zoology and AnthropologyUniversity of GöttingenGöttingenGermany

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