Cellular and Molecular Life Sciences

, Volume 74, Issue 21, pp 3863–3881 | Cite as

Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas

  • Russel J. ReiterEmail author
  • Sergio Rosales-Corral
  • Dun Xian Tan
  • Mei Jie Jou
  • Annia Galano
  • Bing Xu
Multi-author review


Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin’s chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin’s high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.


Free radical-related diseases SIRT3 Melatonin transporters Reactive oxygen species Mitochondrial transition pore Cytochrome c Apoptosis Inner mitochondrial membrane 



This work was supported in part by Grants CMRPD1C0511-3 (from the Chang Gung Memorial Hospital, Taiwan), MOST 105-2320-B-182-011 and MOST 104-2320-B-182-008 (to MJJ).


  1. 1.
    Izon G, Al Zerkle, Williford KH, Farquhar J, Paulton SW, Claire MW (2017) Biological regulation of atmospheric chemistry en route to planetary oxygenation. Proc Natl Acad Sci USA 114:e2571–e2579PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Halliwell B (1996) Free radicals, proteins, DNA: oxidative damage versus redox regulation. Biochem Soc Trans 24:1023–1027PubMedCrossRefGoogle Scholar
  3. 3.
    Fridovich I (2013) Oxygen: how do we stand it? Med Princ Pract 22:131–137PubMedCrossRefGoogle Scholar
  4. 4.
    Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS (1992) Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 5:834–842PubMedCrossRefGoogle Scholar
  5. 5.
    Borg DC (1993) Oxygen free radicals and tissue injury. In: Tarr M, Samson F (eds) Oxygen free radicals in tissue damage. Birkhauser, Cambridge, pp 12–53CrossRefGoogle Scholar
  6. 6.
    Goldstein S, Meyerstein D, Czapski G (1993) The Fenton reagents. Free Radic Biol Med 15:435–445PubMedCrossRefGoogle Scholar
  7. 7.
    Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause or consequence? Lancet 344:721–734PubMedCrossRefGoogle Scholar
  8. 8.
    Kehrer JP (1993) Free radicals as mediators of tissue injury. Crit Rev Toxicol 23:21–48PubMedCrossRefGoogle Scholar
  9. 9.
    Felix JA, Lundgren DG (1973) Electron transport system associated with membranes of Bacillus cereus during vegetative growth and sporulation. J Bacteriol 115:552–559PubMedPubMedCentralGoogle Scholar
  10. 10.
    Liu LN (2016) Distribution and dynamics of electron transport complexes in cyanobacterial thylakoid membranes. Biochim Biophys Acta 1857:256–265PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Moreno SN, Docampo R (1986) Reduction of the metallochromic indicators murexide and tetramethylmurexide to their free radical metabolites by cytoplasmic enzymes and reducing agents. Chem Biol Interact 57:17–25PubMedCrossRefGoogle Scholar
  12. 12.
    Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ (2013) Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res 54:127–138PubMedCrossRefGoogle Scholar
  13. 13.
    Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59:403–419PubMedCrossRefGoogle Scholar
  14. 14.
    Noctor G, Veljovic-Jovanovic S, Foyer CH (2000) Peroxide processing in photosynthesis: antioxidant coupling and redox signaling. Philos Trans R Soc Lond B Biol Sci 355:1465–1475PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Manchester LC, Poeggeler B, Alvarez FL, Ogden GB, Reiter RJ (1995) Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: implications for an ancient antioxidant system. Cell Mol Biol Res 41:391–395PubMedGoogle Scholar
  16. 16.
    Byeon Y, Lee K, Park Y, Park S, Back K (2013) Molecular cloning and functional analysis of serotonin-N-acetyltransferase from the cyanobacterium Synechocystis sp. PCC 6803. J Pineal Res 55:371–376PubMedGoogle Scholar
  17. 17.
    Champney TH, Holtorf AP, Steger RW, Reiter RJ (1984) Concurrent determination of enzymatic activities and substrate concentrations in the melatonin synthetic pathway within the same rat pineal gland. J Neurosci Res 11:59–66PubMedCrossRefGoogle Scholar
  18. 18.
    Stehle JH, Saade A, Rawashdeh O, Ackermann K, Jilg A, Sebesteny T, Maronde E (2011) A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 51:17–43PubMedCrossRefGoogle Scholar
  19. 19.
    Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 80:2587CrossRefGoogle Scholar
  20. 20.
    Hoffman RA, Reiter RJ (1965) Pineal gland: influence of gonads on male hamsters. Science 148:1609–1611PubMedCrossRefGoogle Scholar
  21. 21.
    Reiter RJ, Fraschini F (1969) Endocrine aspects of the mammalian pineal gland: a review. Neuroendocrinology 5:219–255PubMedCrossRefGoogle Scholar
  22. 22.
    Reiter RJ (1972) Evidence for refractoriness of the pituitary-gonadal axis to the pineal gland in golden hamsters and its possible implications for annual reproductive rhythms. Anat Rec 173:365–371PubMedCrossRefGoogle Scholar
  23. 23.
    Dardente H, Lomet D, Robert V, Decourt C, Beltrano M, Pellicer-Rubio MT (2016) Seasonal breeding in mammals: from basic science to applications and back. Theriogenology 86(324):332Google Scholar
  24. 24.
    Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE (2015) Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 22:R183–R204PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K (2017) Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. Int J Mol Sci 18:e843PubMedCrossRefGoogle Scholar
  26. 26.
    Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27:189–200PubMedCrossRefGoogle Scholar
  27. 27.
    Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL (2006) The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 7:423–431PubMedGoogle Scholar
  28. 28.
    Mauriz JL, Collado PS, Veneraso C, Reiter RJ, Gonzalez-Gallego J (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
  29. 29.
    Hosseinzadeh A, Kamrava SK, Joghataei MT, Darabi R, Shakeri-Zadeh A, Shahriari M, Reiter RJ, Ghaznavi H, Mehrzadi S (2016) Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res 61:411–425PubMedCrossRefGoogle Scholar
  30. 30.
    Cardinali DP, Hardeland R (2017) Inflammaging, metabolic syndrome and melatonin: a call for treatment studies. Neuroendocrinology 104:382–397PubMedCrossRefGoogle Scholar
  31. 31.
    Wetterberg L (1978) Melatonin in humans physiological and clinical studies. J Neural Transm 13:289–310Google Scholar
  32. 32.
    Wurtman RJ, Liebermann HR (1985) Melatonin secretion as a mediator of circadian variations in sleep and sleepiness. J Pineal Res 2:301–303PubMedCrossRefGoogle Scholar
  33. 33.
    Kanji S, Mera A, Hutton B, Burry L, Rosenberg E, MacDonald E, Luks V (2016) Pharmacological interventions to improve sleep in hospitalized adults: a systematic review. BMJ Open 6:e12108CrossRefGoogle Scholar
  34. 34.
    Xie Z, Chen F, Li WA, Geng X, Li C, Meng X, Feng Y, Liu W, Yu F (2017) A review of sleep disorders and melatonin. Neurol Res 1:1–7Google Scholar
  35. 35.
    Abdel Moneim AE, Ortiz F, Leonardo-Mendonca RC, Vergano-Villodres R, Guerrero-Martinez JA, Lopez LC, Acuna-Castroviejo D, Escames G (2015) Protective effects of melatonin against oxidative damage induced by Egyptian cobra (Naja haje) crude venom in rats. Acta Trop 143:58–65PubMedCrossRefGoogle Scholar
  36. 36.
    Sharma RD, Katkar GD, Sundaram MS, Paul M, Naveen Kumar SK, Swethakumar B, Hemshekhar M, Girish KS, Kemparaju K (2015) Oxidative stress induced methemoglobinemia is the silent killer during snakebite: a novel and strategic neutralization by melatonin. J Pineal Res 59:240–254PubMedCrossRefGoogle Scholar
  37. 37.
    Xu F, Wang J, Hong F, Wang S, Jin X, Xue T, Jia L, Zhai Y (2017) Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res 62:e12399CrossRefGoogle Scholar
  38. 38.
    Puchalski SS, Green JN, Rasmussen DD (2003) Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 21:163–167PubMedCrossRefGoogle Scholar
  39. 39.
    Peschke E, Bahr I, Muhlbauer E (2015) Experimental and clinical aspects of melatonin and clock genes in diabetes. J Pineal Res 59:1–23PubMedCrossRefGoogle Scholar
  40. 40.
    Gao L, Zhao YC, Liang Y, Lin XH, Tan YJ, Wu DD, Li XZ, Ye BZ, Keng FQ, Sheng JZ, Huang HF (2016) The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment. J Pineal Res 61:340–352PubMedCrossRefGoogle Scholar
  41. 41.
    Hu W, Ma Z, Jiang S, Fan C, Deng C, Yan X, Di S, Lv J, Reiter RJ, Yang Y (2016) Melatonin: the dawning of a treatment for fibrosis? J Pineal Res 60:121–131PubMedCrossRefGoogle Scholar
  42. 42.
    Gonzalez-Fernandez B, Sanchez DI, Crespo I, San Miguel B, Alvarez M, Tunon MJ, Gonzalez-Gallego J (2017) Inhibition of the Sphk1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells. BioFactors 43:272–282PubMedCrossRefGoogle Scholar
  43. 43.
    Reiter RJ, Tan DX, Rosales-Corral SA, Manchester LC (2013) The universal nature, unequal distribution and antioxidant functions of melatonin. Mini Rev Med Chem 13:373–384PubMedGoogle Scholar
  44. 44.
    Garcia JJ, Lopez-Pingarron L, Almeida-Sauza P, Tres A, Escudero P, Garcia-Gil FA, Tan DX, Reiter RJ, Ramirez JM, Bernal-Perez M (2014) Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J Pineal Res 58:225–237CrossRefGoogle Scholar
  45. 45.
    Deng MS, Xu Q, Liu YE, Jiang CH, Zhou H, Gu L (2016) Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury. Exp Ther Med 11:1955–1960PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Mollaoglu H, Topal T, Ozler M, Uysal B, Reiter RJ, Korkmaz A, Oter S (2007) Antioxidant effects of melatonin in rats during chronic exposure to hyperbaric oxygen. J Pineal Res 42:50–54PubMedCrossRefGoogle Scholar
  47. 47.
    Waseem M, Tabassum H, Parnez S (2016) Neuroprotective effects of melatonin as evidenced by abrogation of oxaliplatin induced behavioral alterations, mitochondrial dysfunction and neurotoxicity in rat brain. Mitochondrion 30:168–176PubMedCrossRefGoogle Scholar
  48. 48.
    Reiter RJ, Tan DX, Kim SJ, Qi W (1998) Melatonin as a pharmacological agent against oxidative damage to lipids and DNA. Proc West Pharmacol Soc 41:229–236PubMedGoogle Scholar
  49. 49.
    Chua S, Lee FY, Chiang HJ, Chen KH, Lu HI, Chen YT, Yang CC, Lin KC, Chen YL, Kao GS, Chen CH, Chang HW, Yip HK (2016) The cardioprotective effect of melatonin and exendin-4 in a rat model of cardiorenal syndrome. J Pineal Res 61:438–456PubMedCrossRefGoogle Scholar
  50. 50.
    Venegas C, Garcia JA, Escames G, Ortiz F, Lopez A, Doerrier C, Garcia-Corso L, Lopez LC, Reiter RJ, Acuna-Castroviejo D (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227PubMedCrossRefGoogle Scholar
  51. 51.
    Lowes DA, Webster NR, Murphy MP, Galley HF (2013) Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Brit J Anaesth 110:472–480PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    He C, Wang J, Zhang Z, Yang M, Li Y, Tian X, Ma T, Tao J, Zhu K, Song Y, Ji P, Liu G (2016) Mitochondria synthesize melatonin to ameliorate its function and improve mice oocyte’s quality under in vitro conditions. Int J Mol Sci 17:939–955PubMedCentralCrossRefGoogle Scholar
  53. 53.
    Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ (2015) Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules 20:18886–18906PubMedCrossRefGoogle Scholar
  54. 54.
    Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (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
  55. 55.
    Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54:245–257PubMedCrossRefGoogle Scholar
  56. 56.
    Janjetovic Z, Jarrett SC, Lee EF, Duprey C, Reiter RJ, Slominski AT (2017) Melatonin and its metabolites protect human melanocytes against UVB-induced damage: involvement of NRF2-mediated pathways. Sci Rep 7:1274PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Limson J, Nyokong T, Daya S (1998) The interaction of melatonin and its precursors with aluminum, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. J Pineal Res 24:15–21PubMedCrossRefGoogle Scholar
  58. 58.
    Galano A, Medina ME, Tan DX, Reiter RJ (2015) Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis. J Pineal Res 58:107–116PubMedCrossRefGoogle Scholar
  59. 59.
    Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD, Poeggeler B (1995) Melatonin stimulates glutathione peroxidase. Neurochem Int 26:497–502PubMedCrossRefGoogle Scholar
  60. 60.
    Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. J Biomed Sci 7:444–458PubMedCrossRefGoogle Scholar
  61. 61.
    Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36:1–9PubMedCrossRefGoogle Scholar
  62. 62.
    Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, Honma K, Kendo T (1999) Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med 27:838–847PubMedCrossRefGoogle Scholar
  63. 63.
    Mayo JC, Sainz RM, Gonzalez-Menendez P, Cepas V, Tan DX, Reiter RJ (2017) Melatonin and sirtuins: a “not-so unexpected” relationship. J Pineal Res 62:e12391CrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Yi Y, Tian L, Zhang R, Cao Z, He M, Lu Y, 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
  66. 66.
    Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, Yu L, Liu Z, Yu B, Ren K, Gao E, Yang Y, Liang H, Jin Z, Yu S (2017) Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res 63:e12419CrossRefGoogle Scholar
  67. 67.
    Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:57–63Google Scholar
  68. 68.
    Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR (1994) Melatonin—highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole assessed in vitro. Ann NY Acad Sci 738:419–420PubMedCrossRefGoogle Scholar
  69. 69.
    Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16PubMedCrossRefGoogle Scholar
  70. 70.
    Reiter RJ, Tan DX, Galano A (2014) Melatonin reduces lipid peroxidation and membrane viscosity. Front Physiol 5:377PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Tan DX, Hardeland R, Manchester LC, Poeggler B, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ (2003) Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interaction with the ABTS cation radical. J Pineal Res 34:349–359Google Scholar
  72. 72.
    Galano A (2011) On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals. Phys Chem Chem Phys 13:7178–7188PubMedCrossRefGoogle Scholar
  73. 73.
    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
  74. 74.
    Alvarez-Diduk R, Galano A, Tan DX, Reiter RJ (2015) N-acetylserotonin and 6-hydroxymelatonin against oxidative stress: implications for the overall protection exerted by melatonin. J Phys Chem B 119:8535–8543PubMedCrossRefGoogle Scholar
  75. 75.
    Shin IS, Shin NR, Park JW, Jeon JM, Kwon OK, Kim JS, Lee IC, Kim JC, Oh SR, Ahn KS (2015) Melatonin attenuates neutrophil inflammation and mucus secretion in cigarette smoke-induced chronic obstructive pulmonary disease via the suppression of ErK-Sp1 signaling. J Pineal Res 58:50–60PubMedCrossRefGoogle Scholar
  76. 76.
    Galano A, Castaneda-Arriga R, Perez-Gonzales A, Tan DX, Reiter RJ (2016) Phenolic melatonin related compounds: their role as chemical protectors against oxidative stress. Molecules 21:1442CrossRefGoogle Scholar
  77. 77.
    Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61:253–278PubMedCrossRefGoogle Scholar
  78. 78.
    Galano A, Tan DX, Reiter RJ (2017) Melatonin and related compounds: chemical insights into their protective effects against oxidative stress. Curr Org Chem 21 (in press) Google Scholar
  79. 79.
    Acuna-Castroviejo D, Martin M, Macias M, Escames G, Leon J, Khaldy H, Reiter RJ (2001) Melatonin, mitochondria and cellular bioenergetics. J Pineal Res 30:65–74PubMedCrossRefGoogle Scholar
  80. 80.
    Okatani Y, Wakatsaki A, Reiter RJ (2004) Melatonin and mitochondrial respiration. In: Pandi-Perumal SR, Cardinali DP (eds) Melatonin: biological basis of its function in health and disease. Lander Bioscience, Georgetown, pp 11–24Google Scholar
  81. 81.
    Bromme HJ, Morke W, Peschke D, Ebelt H (2000) Scavenging effect of melatonin on hydroxyl radicals generated by alloxan. J Pineal Res 29:201–208PubMedCrossRefGoogle Scholar
  82. 82.
    Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208PubMedCrossRefGoogle Scholar
  83. 83.
    Pablos MI, Agopito MT, Gutierrez R, Recio JM, Reiter RJ, Barlow-Walden L, Acuna-Castroviejo D, Menendez-Pelaez A (1995) Melatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chickens. J Pineal Res 19:111–115PubMedCrossRefGoogle Scholar
  84. 84.
    Yamamoto H, Yang HW (1996) Preventive effect of melatonin against cyanide-induced seizures and lipid peroxidation in mice. Neurosci Lett 207:89–92PubMedCrossRefGoogle Scholar
  85. 85.
    Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:167–170CrossRefGoogle Scholar
  86. 86.
    Dabbeni S, Floreani M, Franceschini D, Skaper SD, Giusti P (2001) Kainic acid induces selective mitochondrial oxidative phosphorylation enzyme dysfunction in cerebellar granule neurons: protective effects of melatonin and GSH ethyl ester. FASEB J 15:1786–1788Google Scholar
  87. 87.
    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
  88. 88.
    Martin M, Macias M, Escames G, Leon J, Acuna-Castroviejo D (2000) Melatonin but not vitamins C or E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress. FASEB J 14:1677–1679PubMedGoogle Scholar
  89. 89.
    Martin M, Macias M, Escames G, Reiter RJ, Agapito MT, Ortiz GG, Acuna-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
  90. 90.
    Martin M, Macias M, Leon J, Escames G, Khaldy Acuna-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
  91. 91.
    Okatani Y, Wakatsuki A, Reiter RJ, Enzan H, Miyahara Y (2003) Protective effect of melatonin against mitochondrial injury induced by ischemia and reperfusion of rat liver. Eur J Pharmacol 469:145–152PubMedCrossRefGoogle Scholar
  92. 92.
    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
  93. 93.
    Jou MJ, Jou SB, Chen HM, Lin CH, Peng TI (2002) Critical role of mitochondrial reactive oxygen species formation in visible laser irradiation-induced apoptosis in rat brain astrocytes (RBA-1). J Biomed Sci 9:507–516PubMedCrossRefGoogle Scholar
  94. 94.
    Peng TI, Wei YH, Wu HY, Jou MJ (2003) Mitochondrial calcium and ROS mediated apoptosis plays a potential pathogenic role in diseases associated with mitochondrial DNA 4977 bp deletion. Biophys J 84:205aCrossRefGoogle Scholar
  95. 95.
    Jou MJ, Peng TI, Reiter RJ, Jou SB, Wu HY, Wen ST (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
  96. 96.
    Gitto E, Tan DX, Reiter RJ, Karbownik M, Manchester LC, Cuzzocrea S, Fulia F, Barberi I (2001) Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) in liver homogenates. J Pharm Pharmacol 53:1393–1401PubMedCrossRefGoogle Scholar
  97. 97.
    Dimauro S (2004) Mitochondrial diseases. Biochim Biophys Acta 1658:80–88PubMedCrossRefGoogle Scholar
  98. 98.
    Jou MJ, Peng TI, Wu HY, Wei YH (2005) Enhanced generation of mitochondrial reactive oxygen species in cybrids containing 4977-bp mitochondrial DNA deletion. Ann NY Acad Sci 1042:221–228PubMedCrossRefGoogle Scholar
  99. 99.
    Peng TI, Yu PR, Chen JY, Wang HL, Wu HY, Wei YH, Jou MJ (2006) Visualizing common deletion of mitochondrial DNA-augmented mitochondrial reactive oxygen species generation and apoptosis upon oxidative stress. Biochem Biophys Acta 1762:241–255PubMedGoogle Scholar
  100. 100.
    Jou MJ, Peng TI, Yu PZ, Jou SB, Reiter RJ, Chen JY, Wu HY, Chen CC, Hsu LF (2007) Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis. J Pineal Res 43:389–403PubMedCrossRefGoogle Scholar
  101. 101.
    Jou MJ, Peng TI, Hsu LF, Jou SB, Reiter RJ, Yang CM, Chiao CC, Lin YF, Chen CC (2010) Visualization of melatonin’s multiple mitochondrial levels of protection against mitochondrial Ca2+-mediated permeability transition and beyond in rat brain astrocytes. J Pineal Res 48:20–38PubMedCrossRefGoogle Scholar
  102. 102.
    Ozaki Y, Lynch HJ (1976) Presence of melatonin in plasma and urine of pinealectomized rats. Endocrinology 99:641–644PubMedCrossRefGoogle Scholar
  103. 103.
    Mori Y, Okamura H (1986) Effects of timed melatonin infusion on prolactin secretion in pineal denervated goats. J Pineal Res 3:77–86PubMedCrossRefGoogle Scholar
  104. 104.
    Hoffman RA, Reiter RJ (1965) Influence of compensatory mechanisms and the pineal gland on dark-induced gonadal atrophy in male hamsters. Nature 207:658–659PubMedCrossRefGoogle Scholar
  105. 105.
    Reiter RJ, Hester RJ (1966) Interrelationships of the pineal gland, the superior cervical ganglia and the photoperiod in the regulation of the endocrine systems of hamsters. Endocrinology 79:1168–1170PubMedCrossRefGoogle Scholar
  106. 106.
    Quay MB (1974) Temporal mitotic patterns around a brain lesion: cellular and regional asynchronism and an effect of pinealectomy. Chronobiologia 1:237–258PubMedGoogle Scholar
  107. 107.
    Reiter RJ, Tan DX, Kim SK, Cruz MH (2014) Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow–Robin perivascular spaces. Brain Struct Funct 219:1873–1887PubMedCrossRefGoogle Scholar
  108. 108.
    Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002) Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 143:84–90PubMedCrossRefGoogle Scholar
  109. 109.
    Vriend J, Reiter RJ (2015) Melatonin feedback on clock genes: a theory involving the proteasome. J Pineal Res 58:1–11PubMedCrossRefGoogle Scholar
  110. 110.
    Matsumura R, Node K, Akaski M (2016) Estimation methods for human circadian phase by use of peripheral tissues. Hypertens Res 39:623–627PubMedCrossRefGoogle Scholar
  111. 111.
    Muller MJ, Geisler C (2017) From the past to future: from energy expenditure to energy intake to energy expenditure. Eur J Clin Nutr 71:358–364PubMedCrossRefGoogle Scholar
  112. 112.
    Rosales-Corral SA, Acuna-Castroviejo D, Coto-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, Korkmaz A, Tan DX, Reiter RJ (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202PubMedCrossRefGoogle Scholar
  113. 113.
    Dong Y, Fan C, Hu W, Jiang S, Ma Z, Yan X, Deng C, Di S, Xin Z, Wu G, Yang Y, Reiter RJ, Liang G (2016) Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. J Pineal Res 60:253–262PubMedCrossRefGoogle Scholar
  114. 114.
    Salim S (2017) Oxidative stress and the central nervous system. J Pharmacol Exp Ther 380:201–205Google Scholar
  115. 115.
    Cardinali DP, Rosner JM (1971) Retinal localization of the hydroxyindole-O-methyl transferase (HIOMT) in the rat. Endocrinology 89:301–303PubMedCrossRefGoogle Scholar
  116. 116.
    Tan DX, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (1999) High levels of melatonin in the bile of mammals. Life Sci 65:2523–2529PubMedCrossRefGoogle Scholar
  117. 117.
    Reiter RJ, Rosales-Corral SA, Manchester LC, Liu X, Tan DX (2014) Melatonin in the biliary tract and liver: health implications. Curr Pharm Res 20:4788–4801CrossRefGoogle Scholar
  118. 118.
    Dubbels R, Reiter RJ, Klenke E, Goebel A, Schnakenberg E, Ehlers C, Schiwara HW, Schloot W (1995) Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 18:28–31PubMedCrossRefGoogle Scholar
  119. 119.
    Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ (1995) Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors n vertebrates. Biochem Mol Bio Int 35:627–634Google Scholar
  120. 120.
    Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A (2015) Phytomelatonin: assisting plants to survive and thrive. Molecules 20:7396–7437PubMedCrossRefGoogle Scholar
  121. 121.
    Arnao MB, Ruiz-Hernandez J (2015) Function of melatonin in plants: a review. J Pineal Res 59:133–150PubMedCrossRefGoogle Scholar
  122. 122.
    Archibald JM (2015) Endosymbiosis and eukaryotic cell evolution. Curr Biol 25:R911–R921PubMedCrossRefGoogle Scholar
  123. 123.
    Bajwa VS, Shukla MR, Sherif SM, Murch SJ, Saxena PK (2014) Role of melatonin in alleviating cold stress in Arabidopsis thaliana. J Pineal Res 56:238–245PubMedCrossRefGoogle Scholar
  124. 124.
    Shi H, Qian Y, Tan DX, Reiter RJ (2015) Melatonin reduces the transcripts of CBF-DREB1S and their involvement in both abiotic and biotic stresses in Arabidopsis. J Pineal Res 59:334–342PubMedCrossRefGoogle Scholar
  125. 125.
    Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, Rosales-Corral SA, Tan DX, Reiter RJ (2014) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. Cell Mol Life Sci 71:2997–3025PubMedCrossRefGoogle Scholar
  126. 126.
    Kerenyi NA, Sotonyi P, Somogyi E (1975) Localizing acetylserotonin transferase by electron microscopy. Histochemistry 46:77–80CrossRefGoogle Scholar
  127. 127.
    Kerenyi NA, Balogh I, Somogyi E, Sotonyi P (1979) Cytochemical investigation of acetylserotonin-transferase activity in the pineal gland. Cell Mol Biol Incl Cyto Enzymol 25:259–262PubMedGoogle Scholar
  128. 128.
    Tamura H, Takasaki A, Ichias M, Taniquchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Mori M, Ishikawa H, Reiter RJ (2008) Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res 44:222–226CrossRefGoogle Scholar
  129. 129.
    Sakaguchi K, Itoh MT, Takahashi N, Tarumi W, Ishizuka B (2013) The rat oocyte synthesizes melatonin. Reprod Fertil Rev 25:674–682CrossRefGoogle Scholar
  130. 130.
    Coelho LA, Peres R, Amaral FG, Reiter RJ, Cipolla-Neto J (2015) Daily differential expression of melatonin-related genes and clock genes in rat cumulus-oocyte complex: changes after pinealectomy. J Pineal Res 58:490–499PubMedCrossRefGoogle Scholar
  131. 131.
    Back K, Tan DX, Reiter RJ (2016) Melatonin biosynthesis in plants: multiple pathways catalyze tryptophan to melatonin in the cytoplasm or chloroplasts. J Pineal Res 61:426–437PubMedCrossRefGoogle Scholar
  132. 132.
    Zheng X, Tan DX, Allan AC, Zuo B, Zhao Y, Reiter RJ, Wang L, Wang Z, Guo Y, Zhou J, Shan D, Li Q, Han Z, Kong J (2017) Chloroplastic biosynthesis of melatonin and its involvement in protection of plants from salt stress. Sci Rep 7:41236PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Byeon Y, Lee HY, Lee K, Back K (2014) Cellular localization and kinetics of the rice melatonin biosynthetic enzymes SNAT and ASMT. J Pineal Res 56:107–114PubMedCrossRefGoogle Scholar
  134. 134.
    Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ (2013) Functional roles of melatonin in plants and perspectives in nutritional and agricultural sciences. J Exp Bot 63:577–597CrossRefGoogle Scholar
  135. 135.
    Wang L, Feng L, Zheng X, Guo Y, Zhou F, Shan D, Liu X, Kong J (2017) Plant mitochondria synthesize melatonin and enhance the tolerance of plants to drought stress. J Pineal Res 69:e12429CrossRefGoogle Scholar
  136. 136.
    Tan DX, Hardeland R, Back K, Manchester LC, Alatorre-Jimenez MA, Reiter RJ (2016) A hypothesis concerning the predominant melatonin synthetic pathway: inversion of the terminal enzymatic steps. J Pineal Res 61:27–40PubMedCrossRefGoogle Scholar
  137. 137.
    Acuna-Castroviejo D, Lopez LC, Escames G, Lopez A, Garcia JJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240PubMedCrossRefGoogle Scholar
  138. 138.
    Yu L, Liang H, Lu Z, Zhao G, Zhai M, Yang Y, Yang J, Yi D, Chen W, Wang X, Duan W, Jin Z, Yu S (2015) Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies. J Pineal Res 59:420–433PubMedCrossRefGoogle Scholar
  139. 139.
    Stefanova NA, Maksimova KY, Kiseleva E, Rudnitskaya EA, Muraleva NA, Kolosova NG (2015) Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer’s disease-like pathology. J Pineal Res 59:163–177PubMedCrossRefGoogle Scholar
  140. 140.
    Chuang JI, Pan IL, Hsieh CY, Huang CY, Chen PC, Shin JW (2016) Melatonin prevents the Drp 1-dependent mitochondrial fission and oxidative insult in the cortical neurons after MPP treatment. J Pineal Res 61:230–240PubMedCrossRefGoogle Scholar
  141. 141.
    Prieto-Dominguez N, Ordonez R, Fernandez A, Mendez-Blanco C, Baulies A, Garcia-Ruiz L, Fernandez-Checa JC, Mauriz JL, Gonzalez-Gallego J (2016) Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. J Pineal Res 61:396–407PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Ueck M, Troiani ME, Reiter RJ (1988) Transient reduction in pineal melatonin levels but not N-acetyltransferase activity in rats to swim for 15 minutes at night. Neuroendocrinol Lett 10:81–90Google Scholar
  143. 143.
    Wu W, Reiter RJ, Troiani ME, Vaughan GM (1987) Elevated daytime rat pineal and serum melatonin levels induced by isoproterenol are depressed by swimming. Life Sci 41:1473–1479PubMedCrossRefGoogle Scholar
  144. 144.
    Troiani ME, Reiter RJ, Vaughan MK, Oaknin S, Vaughan GM (1987) Swimming depresses nighttime melatonin content without changing N-acetyltransferase activity in the rat pineal gland. Neuroendocrinology 47:55–60CrossRefGoogle Scholar
  145. 145.
    Sewerynek E, Melchiorri D, Chen LD, Reiter RJ (1995) Melatonin reduces both basal and bacterial lipopolysaccharide-induced lipid peroxidation. Free Radic Biol Med 19:903–909PubMedCrossRefGoogle Scholar
  146. 146.
    Sewerynek E, Ortiz GG, Reiter RJ, Pablos MI, Melchiorri D, Daniels WMV (1996) Lipopolysaccharide-induced DNA damage is greatly reduced in rats treated with the pineal hormone melatonin. Mol Cell Endocrinol 17:183–188CrossRefGoogle Scholar
  147. 147.
    Andrabi SA et al (2008) Direct inhibition of the mitochondrial transition pore: a possible mechanism for antiapoptotic effects of melatonin. FASEB J 18:869–887Google Scholar
  148. 148.
    Le Bars D, Thivolle P, Vitte RA, Bojkowski C, Chazot G, Arendt J, Frackowiak RS, Claustrat B (1991) PET and plasma pharmacokinetic studies after bolus intravenous administration of [11C]melatonin in humans. Int J Radiat Appl Instrum B 18:357–362CrossRefGoogle Scholar
  149. 149.
    Costa EJ, Shida CS, Baggi MH, Ito AS, Laney-Fruend MT (1997) How melatonin interacts with lipid bilayers: a study by fluorescence and ESR spectroscopies. FEBS Lett 416:103–106PubMedCrossRefGoogle Scholar
  150. 150.
    Hevia D, Gonzalez-Menendez P, Quiros-Gonzalez L, Miar A, Rodriguez-Garcia A, Tan DX, Reiter RJ, Mayo JC, Sainz RM (2015) Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer. J Pineal Res 58:234–250PubMedCrossRefGoogle Scholar
  151. 151.
    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 62:e12390CrossRefGoogle Scholar
  152. 152.
    Pozo D, Reiter RJ, Calvo JR, Guerrero JM (1997) Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem 64:430–442CrossRefGoogle Scholar
  153. 153.
    Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI (2003) Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 8:d1093–d1108PubMedCrossRefGoogle Scholar
  154. 154.
    Boutin JA (2016) Quinone reductase 2 as a promising of target melatonin therapeutic actions. Expert Opin Ther Targets 20:303–317PubMedCrossRefGoogle Scholar
  155. 155.
    Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H (2011) The melatonin MT1 receptor axis modulates mutant Huntington-mediated toxicity. J Neurosci 31:14496–14507PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Brealey D, Singer M (2003) Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep 5:365–371PubMedCrossRefGoogle Scholar
  157. 157.
    Crouser ED (2004) Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4:729–741PubMedCrossRefGoogle Scholar
  158. 158.
    Volt H, Garcia JA, Doerrier C, Diaz-Casado ME, Guerra-Librero A, Lopez LC, Escames G, Tresguerres JA, Acuna-Castroviejo D (2016) Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res 60:193–205PubMedCrossRefGoogle Scholar
  159. 159.
    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski P, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219–223PubMedCrossRefGoogle Scholar
  160. 160.
    Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286:R491–R497PubMedCrossRefGoogle Scholar
  161. 161.
    Gellerich FN, Trumbeckaite S, Hertel K, Zierz S, Müller-Werdan V, Werdan K, Redl H, Schlag G (1999) Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock 11:336–341PubMedCrossRefGoogle Scholar
  162. 162.
    Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, Cordaro S, Corona G, Trimarchi G, Barberi I (2001) Effects of melatonin treatment in septic newborns. Pediatr Res 50:756–760PubMedCrossRefGoogle Scholar
  163. 163.
    Escames G, Acuna-Castroviejo D, Lopez LC, Maldonado MD, Sanchez-Hidalgo M, Lun J, Reiter RJ (2006) The pharmacological utility of melatonin in the treatment of septic shock. J Pharm Pharmacol 58:1153–1165PubMedCrossRefGoogle Scholar
  164. 164.
    Reiter RJ, Carneiro RC, Oh CS (1997) Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res 29:363–372PubMedCrossRefGoogle Scholar
  165. 165.
    Wu CC, Chiao CW, Hsiao G, Chen A, Yen MH (2001) Melatonin prevents endotoxin-induced circulatory failure. J Pineal Res 30:147–156PubMedCrossRefGoogle Scholar
  166. 166.
    Leon J, Acuna-Castroviejo D, Escames G, Tan DX, Reiter RJ (2005) Melatonin mitigates mitochondrial malfunction. J Pineal Res 38:1–9PubMedCrossRefGoogle Scholar
  167. 167.
    Tan DX, Manchester LC, Qin L, Reiter RJ (2016) Melatonin: a mitochondrial targeting molecule involving mitochondrial functioning and dynamics. Int J Mol Sci 17:2124PubMedCentralCrossRefGoogle Scholar
  168. 168.
    Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RAJ, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596PubMedCrossRefGoogle Scholar
  169. 169.
    Echtay KS, Murphy MP, Smith RAJ, Talbot DA, Brand MD (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277:47129–47135PubMedCrossRefGoogle Scholar
  170. 170.
    Jauslin ML, Meier T, Smith RAJ, Murphy MP (2003) Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 17:1972–1974PubMedGoogle Scholar
  171. 171.
    Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ (2015) Protective effects of mitochondria and mitochondria-targeted antioxidants against oxidative stress. Curr Med Chem 22:2690–2711PubMedCrossRefGoogle Scholar
  172. 172.
    Hardeland R (2005) Antioxidative protection by melatonin: multiplicity of mechanisms from radical neutralization to radical avoidance. Endocrine 27:119–130PubMedCrossRefGoogle Scholar
  173. 173.
    Muxel SM, Laranjeira-Silva MF, Carvalho-Sousa CE, Floeter-Winter LM, Markus RP (2016) The ReIA/cRel nuclear factor-κB (NF-κB) dimer, crucial for inflammation resolution, mediates the transcription of the key enzyme in melatonin synthesis in RAW 264.7 macrophages. J Pineal Res 60:394–404PubMedCrossRefGoogle Scholar
  174. 174.
    Lin C, Chao H, Li Z, Xu X, Liu Y, Hou L, Liu N, Ji J (2016) Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy. J Pineal Res 61:177–186PubMedCrossRefGoogle Scholar
  175. 175.
    Supinski GS, Murphy MP, Callahan LA (2009) MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 297:R1095–R1102PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG (2014) Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochem Biophys Acta 1842:1282–1294PubMedGoogle Scholar
  177. 177.
    Matthews RT, Yang L, Browne S, Baik M, Beal MF (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 95:8892–8897PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Smith RAJ, Porteous AM, Coulter CV, Murphy MP (1999) Selective targeting of an antioxidant in mitochondria. Eur J Biochem 263:709–716PubMedCrossRefGoogle Scholar
  179. 179.
    Doerrier C, Garcia JA, Volt H, Diaz-Casado ME, Luna-Sanchez M, Fernandez-Gil B, Escames G, Lopez LC, Acuna-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
  180. 180.
    Oyewole AO, Birch-Machin MA (2015) Mitochondria-targeted antioxidants. FASEB J 29:4766–4771PubMedCrossRefGoogle Scholar
  181. 181.
    Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdisc Toxicol 1:101–113CrossRefGoogle Scholar
  182. 182.
    Cippolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ (2014) Melatonin, energy metabolism, and obesity. J Pineal Res 56:371–381CrossRefGoogle Scholar
  183. 183.
    Sharma S, Singh H, Ahmad N, Mishra P, Tiwari A (2015) The role of melatonin in diabetes: therapeutic implications. Arch Endocrinol Metab 59:391–399PubMedCrossRefGoogle Scholar
  184. 184.
    Xu S, Pi H, Zhang L, Zhang N, Li Y, Zhang H, Tang J, Li H, Feng M, Deng P, Guo P, Tian L, Xie J, He M, Lu Y, Zhang M, Zhang Y, Wang W, Reiter RJ, Yu Z, Zhou Z (2016) Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. J Pineal Res 60:291–302PubMedCrossRefGoogle Scholar
  185. 185.
    Reiter RJ, Tan DX, Galano A (2014) Melatonin: exceeding expectations. Physiology (Bethesda) 29:325–333Google Scholar
  186. 186.
    Sadeghian M, Mastrolia V, Rezaei Haddad A, Mosley A, Mullali G, Schiza D, Sajic M, Hargreaves I, Heales S, Duchen MR, Smith KJ (2016) Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis. Sci Rep 6:33249PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Mao P, Reddy PH (2010) Is multiple sclerosis: a mitochondrial disease? Biochim Biophys Acta 1802:66–79PubMedCrossRefGoogle Scholar
  188. 188.
    Kashani IR, Rajabi Z, Akbari M, Hassanzadeh G, Mohseni A, Eramsadati MK, Rafiee K, Beyer C, Kipp M, Zendedel A (2014) Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp Brain Res 232:2835–2846PubMedCrossRefGoogle Scholar
  189. 189.
    Lopez-Gonzalez A, Alvarez-Sanchez N, Lardone PJ, Cruz-Chamorro L, Martinez-Lopez A, Guerrero JM, Reiter RJ, Carrillo-Vico A (2015) Melatonin improves primary progressive multiple sclerosis: a case report. J Pineal Res 58:173–177PubMedCrossRefGoogle Scholar
  190. 190.
    Swerdlow RH, Koppel S, Weidling I, Hayley C, Ji Y, Wilkins HM (2017) Mitochondria, cybrids, aging and Alzheimer’s disease. Prog Mol Biol Transl Sci 146:259–302PubMedCrossRefGoogle Scholar
  191. 191.
    Giannoccaro MP, La Morgia C, Rizzo G, Carelli V (2017) Mitochondrial DNA and primary mitochondrial dysfunction in Parkinson’s disease. Mov Disord 32:346–363PubMedCrossRefGoogle Scholar
  192. 192.
    Liot G, Valette J, Pepin J, Flament J, Braulliet E (2017) Energy defects in Huntington’s disease: why “in vivo” evidence matters. Biochem Biophys Res Commun 483:1084–1095PubMedCrossRefGoogle Scholar
  193. 193.
    Chahbouni M, Escames G, Venegas C, Sevilla B, Garcia JA, Lopez LC, Munoz-Hoyos A, Molina-Carballo A, Acuna-Castroviejo D (2010) Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy. J Pineal Res 48:282–289PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Russel J. Reiter
    • 1
    Email author
  • Sergio Rosales-Corral
    • 2
  • Dun Xian Tan
    • 1
  • Mei Jie Jou
    • 3
    • 4
  • Annia Galano
    • 5
  • Bing Xu
    • 1
  1. 1.Department of Cell Systems and AnatomyUT Health San AntonioSan AntonioUSA
  2. 2.Centro de Investigacion Biomedica de OccidenteDel Instituto Mexicana del Seguro SocialGuadalajaraMexico
  3. 3.Department of Physiology and Pharmacology, College of MedicineChang Gung UniversityTaoyüanTaiwan
  4. 4.Department of Neurology, Kee-Lung Medical CenterChang Gung Memorial HospitalKeelungTaiwan
  5. 5.Departemento de QuimicaUninversidad Autonoma Metropolitana-IztapalapaMexico CityMexico

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