Cellular and Molecular Life Sciences

, Volume 74, Issue 21, pp 3927–3940 | Cite as

Melatonin transport into mitochondria

  • Juan C. MayoEmail author
  • Rosa M. Sainz
  • Pedro González-Menéndez
  • David Hevia
  • Rafael Cernuda-Cernuda
Multi-author review


Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.


Melatonin Mitochondria GLUT transporters MTNR Uptake Diffusion 



This work was supported by funding from ‘Ministerio de Economía y Competitividad’ (Grant# MINECO-17-BFU2016-79139-R). PGM acknowledges sponsorship from Ministerio de Educación, Cultura y Deporte (AP2012-4924).


  1. 1.
    Pelham RW (1975) A serum melatonin rhythm in chickens and its abolition by pinealectomy. Endocrinology 96:543–546PubMedCrossRefGoogle Scholar
  2. 2.
    Reiter RJ, Rollag MD, Panke ES, Banks AF (1978) Melatonin: reproductive effects. J Neural Transm Suppl 13:209–223Google Scholar
  3. 3.
    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
  4. 4.
    Lerner AB, Case JD, Heinzelman RV (1959) Structure of melatonin. J Am Chem Soc 81:6084–6085CrossRefGoogle Scholar
  5. 5.
    Fao C (1912) Hypertrophie des testicules et de la crete après l’extirpation de la glande pineale chez le coq. Arch Ital Biol 57:233–252Google Scholar
  6. 6.
    Kitay JI (1954) Effects of pinealectomy on ovary weight in immature rats. Endocrinology 54:114–116PubMedCrossRefGoogle Scholar
  7. 7.
    Wurtman RJ, Axelrod J, Phillips LS (1963) Melatonin synthesis in the pineal gland: control by light. Science 142:1071–1073PubMedCrossRefGoogle Scholar
  8. 8.
    Hoffman RA, Reiter RJ (1965) Pineal gland influence on gonads of male Hamsters. Science 148:1609–1611PubMedCrossRefGoogle Scholar
  9. 9.
    Pévet P (2002) Melatonin. Dialogues Clin Neurosci 4:57–72PubMedPubMedCentralGoogle Scholar
  10. 10.
    Maestroni GJM (1998) The photoperiod transducer melatonin and the immune-hematopoietic system. J Photochem Photobiol B Biol 43:186–192CrossRefGoogle Scholar
  11. 11.
    Carrillo-Vico A, Lardone PJ, Álvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM (2013) Melatonin: buffering the immune system. Int J Mol Sci 14:8638–8683PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bartsch C, Bartsch H, Bellmann O, Lippert TH (1991) Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism. Cancer 67:1681–1684PubMedCrossRefGoogle Scholar
  13. 13.
    Blask DE, Sauer LA, Dauchy RT (2002) Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2:113–132PubMedCrossRefGoogle Scholar
  14. 14.
    Quay WB (1965) Retinal and pineal hydroxyindole-o-methyl transferase activity in vertebrates. Life Sci 4:983–991PubMedCrossRefGoogle Scholar
  15. 15.
    Cardinali DP, Wurtman RJ (1972) Hydroxyindole-O-methyl transferases in rat pineal, retina and Harderian gland. Endocrinology 91:247–252PubMedCrossRefGoogle Scholar
  16. 16.
    Huether G, Poeggeler B, Reimer A, George A (1992) Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 51:945–953PubMedCrossRefGoogle Scholar
  17. 17.
    Finocchiaro LM, Arzt ES, Fernández-Castelo S, Criscuolo M, Finkielman S, Nahmod VE (1988) Serotonin and melatonin synthesis in peripheral blood mononuclear cells: stimulation by interferon-gamma as part of an immunomodulatory pathway. J Interferon Res 8:705–716PubMedCrossRefGoogle Scholar
  18. 18.
    Tijmes M, Pedraza R, Valladares L (1996) Melatonin in the rat testis: evidence for local synthesis. Steroids 61:65–68PubMedCrossRefGoogle Scholar
  19. 19.
    Tan DX, Manchester LC, Reiter RJ, Qi WB, Zhang M, Weintraub ST et al (1999) Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta Gen Subj 1472:206–214CrossRefGoogle Scholar
  20. 20.
    Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J, Szczesniewski A et al (2002) Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J 16:896–898PubMedGoogle Scholar
  21. 21.
    Oblap R, Olszańska B (2003) Presence and developmental regulation of serotonin N-acetyltransferase transcripts in oocytes and early quail embryos (Coturnix coturnix japonica). Mol Reprod Dev 65:132–140PubMedCrossRefGoogle Scholar
  22. 22.
    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
  23. 23.
    Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, Carrascosa-Salmoral MP et al (2007) Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci 64:781–790PubMedCrossRefGoogle Scholar
  24. 24.
    Shimozuma M, Tokuyama R, Tatehara S, Umeki H, Ide S, Mishima K et al (2011) Expression and cellular localization of melatonin-synthesizing enzymes in rat and human salivary glands. Histochem Cell Biol 135:389–396PubMedCrossRefGoogle Scholar
  25. 25.
    Gonzalez-Arto M, Hamilton TRDS, Gallego M, Gaspar-Torrubia E, Aguilar D, Serrano-Blesa E et al (2016) Evidence of melatonin synthesis in the ram reproductive tract. Andrology 4:163–171PubMedCrossRefGoogle Scholar
  26. 26.
    Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC et al (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 71:2997–3025PubMedCrossRefGoogle Scholar
  27. 27.
    Pöggeler B, Balzer I, Hardeland R, Lerchl A (1991) Pineal hormone melatonin oscillates also in the dinoflagellate Gonyaulax polyedra. Naturwissenschaften 78:268–269CrossRefGoogle Scholar
  28. 28.
    Balzer I (1996) Recent progress in understanding the temporal behavior of unicellular organisms. Braz J Med Biol Res 29:95–99PubMedGoogle Scholar
  29. 29.
    Tanaka D, Furusawa K, Kameyama K, Okamoto H, Doi M (2007) Melatonin signaling regulates locomotion behavior and homeostatic states through distinct receptor pathways in Caenorhabditis elegans. Neuropharmacology 53:157–168PubMedCrossRefGoogle Scholar
  30. 30.
    Tosches MA, Bucher D, Vopalensky P, Arendt D (2014) Melatonin signaling controls circadian swimming behavior in marine zooplankton. Cell 159:46–57PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Finocchiaro L, Callebert J, Launay JM, Jallon JM (1988) Melatonin biosynthesis in Drosophila: its nature and its effects. J Neurochem 50:382–387PubMedCrossRefGoogle Scholar
  32. 32.
    Vivien-Roels B, Pevet P, Beck O, Fevre-Montange M (1984) Identification of melatonin in the compound eyes of an insect, the locust (Locusta migratoria), by radioimmunoassay and gas chromatography-mass spectrometry. Neurosci Lett 49:153–157PubMedCrossRefGoogle Scholar
  33. 33.
    Schwarzenberger A, Christjani M, Wacker A (2014) Longevity of Daphnia and the attenuation of stress responses by melatonin. BMC Physiol 14:8PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Tilden AR, Rasmussen P, Awantang RM, Furlan S, Goldstein J, Palsgrove M et al (1997) Melatonin cycle in the fiddler crab Uca pugilator and influence of melatonin on limb regeneration. J Pineal Res 23:142–147PubMedCrossRefGoogle Scholar
  35. 35.
    Hardeland R (2015) Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions. J Exp Bot 66:627–646PubMedCrossRefGoogle Scholar
  36. 36.
    Tan DX, Pöeggeler B, Reiter RJ, Chen LD, Chen S, Lucien MC et al (1993) The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Lett 70:65–71PubMedCrossRefGoogle Scholar
  37. 37.
    Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM et al (2010) The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev 85:607–623PubMedGoogle Scholar
  38. 38.
    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
  39. 39.
    Vakkuri O, Lamsa E, Rahkamaa E, Ruotsalainen H, Leppaluoto J (1984) Iodinated melatonin: preparation and characterization of the molecular structure by mass and 1H NMR spectroscopy. Anal Biochem 142:284–289PubMedCrossRefGoogle Scholar
  40. 40.
    Vakkuri O, Leppaluoto J, Vuolteenaho O (1984) Development and validation of a melatonin radioimmunoassay using radioiodinated melatonin as tracer. Eur J Endocrinol 106:152–157CrossRefGoogle Scholar
  41. 41.
    Laudon M, Zisapel N (1986) Characterization of central melatonin receptors using 125I-melatonin. FEBS Lett 197:9–12PubMedCrossRefGoogle Scholar
  42. 42.
    Duncan MJ, Takahashi JS, Dubocovich ML (1986) Characterization of 2-[125I]iodomelatonin binding sites in hamster brain. Eur J Pharmacol 132:333–334PubMedCrossRefGoogle Scholar
  43. 43.
    Weaver DR, Namboodiri MAA, Reppert SM (1988) Iodinated melatonin mimics melatonin action and reveals discrete binding sites in fetal brain. FEBS Lett 228:123–127PubMedCrossRefGoogle Scholar
  44. 44.
    Williams LM, Morgan PJ (1988) Demonstration of melatonin-binding sites on the pars tuberalis of the rat. J Endocrinol 119:R1–R3PubMedCrossRefGoogle Scholar
  45. 45.
    Weaver DR, Reppert SM (1990) Melatonin receptors are present in the ferret pars tuberalis and pars distalis, but not in brain. Endocrinology 127:2607–2609PubMedCrossRefGoogle Scholar
  46. 46.
    Rivkees SA, Carlson LL, Reppert SM (1989) Guanine nucleotide-binding protein regulation of melatonin receptors in lizard brain. Proc Natl Acad Sci USA 86:3882–3886PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Dubocovich ML, Shankar G, Mickel M (1989) 2-[125I]Iodomelatonin labels sites with identical pharmacological characteristics in chicken brain and chicken retina. Eur J Pharmacol 162:289–299PubMedCrossRefGoogle Scholar
  48. 48.
    Reppert SM, Weaver DR, Rivkees SA, Stopa EG (1988) Putative melatonin receptors in a human biological clock. Science 242:78–81PubMedCrossRefGoogle Scholar
  49. 49.
    Blazynski C, Dubocovich ML (1991) Localization of 2-[125I]Iodomelatonin binding sites in mammalian retina. J Neurochem 56:1873–1880PubMedCrossRefGoogle Scholar
  50. 50.
    Dubocovich ML, Takahashi JS (1987) Use of 2-[125I]iodomelatonin to characterize melatonin binding sites in chicken retina. Proc Natl Acad Sci USA 84:3916–3920PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Menéndez-Pelaez A, López-González MA, Guerrero JM (1993) Melatonin binding sites in the Harderian gland of Syrian hamsters: sexual differences and effect of castration. J Pineal Res 14:34–38PubMedCrossRefGoogle Scholar
  52. 52.
    Bubenik GA, Niles LP, Pang SF, Pentney PJ (1993) Diurnal variation and binding characteristics of melatonin in the mouse brain and gastrointestinal tissues. Comp Biochem Physiol Part C Comp 104:221–224CrossRefGoogle Scholar
  53. 53.
    Wan Q, Pang SF (1995) 2-[125I]iodomelatonin binding sites in the quail liver: characterization and the effect of guanosine 5′-O-(3-thiotriphosphate). Neurosignals 4:24–31CrossRefGoogle Scholar
  54. 54.
    Pang SF, Ayre EA, Poon A, Pang CS, Yuan H, Wang ZP et al (1993) Effects of guanosine 5′-O-(3-thiotriphosphate) on 2-[125I]lodomelatonin binding in the chicken lung, brain and kidney: hypothesis of different subtypes of high affinity melatonin receptors. Neurosignals 2:27–36CrossRefGoogle Scholar
  55. 55.
    Pang CS, Brown GM, Tang PL, Cheng KM, Pang SF (1993) 2-[125I]iodomelatonin binding sites in the lung and heart: a link between the photoperiodic signal, melatonin, and the cardiopulmonary system. Biol Signals 2:228–236PubMedCrossRefGoogle Scholar
  56. 56.
    Lopez-Gonzalez MA, Calvo JR, Osuna C, Guerrero JM (1992) Interaction of melatonin with human lymphocytes: evidence for binding sites coupled to potentiation of cyclic AMP stimulated by vasoactive intestinal peptide and activation of cyclic GMP. J Pineal Res 12:97–104PubMedCrossRefGoogle Scholar
  57. 57.
    Rafii-el-idrissi M, Calvo JR, Pozo D, Harmouch A, Guerrero Juan M (1995) Specific binding of 2-[125I]iodomelatonin by rat splenocytes: characterization and its role on regulation of cyclic AMP production. J Neuroimmunol 57:171–178PubMedCrossRefGoogle Scholar
  58. 58.
    Clemens JW, Jarzynka MJ, Witt-Enderby PA (2001) Down-regulation of mt1 melatonin receptors in rat ovary following estrogen exposure. Life Sci 69:27–35PubMedCrossRefGoogle Scholar
  59. 59.
    Yie SM, Niles LP, Younglai EV (1995) Melatonin receptors on human granulosa cell membranes. J Clin Endocrinol Metab 80:1747–1749PubMedGoogle Scholar
  60. 60.
    Ayre EA, Pang SF (1994) 2-[125I]Iodomelatonin binding sites in the testis and ovary: putative melatonin receptors in the gonads. Neurosignals 3:71–84CrossRefGoogle Scholar
  61. 61.
    Vera H, Tijmes M, Ronco AM, Valladares LE (1993) Melatonin binding sites in interstitial cells from immature rat testes. Biol Res 26:337–340PubMedGoogle Scholar
  62. 62.
    Ayre EA, Yuan H, Pang SF (1992) The identification of 125I-labelled iodomelatonin-binding sites in the testes and ovaries of the chicken (Gallus domesticus). J Endocrinol 133:5–11PubMedCrossRefGoogle Scholar
  63. 63.
    Arendt J (1996) Melatonin. Br Med J 312:1242–1243CrossRefGoogle Scholar
  64. 64.
    Li D, Smith D, Hardeland R, Yang M, Xu H, Zhang L et al (2013) Melatonin receptor genes in vertebrates. Int J Mol Sci 14:11208–11223PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185PubMedCrossRefGoogle Scholar
  66. 66.
    Migaud M (2005) MTNR1A Melatonin receptors in the ovine premammillary hypothalamus: day-night variation in the expression of the transcripts. Biol Reprod 72:393–398PubMedCrossRefGoogle Scholar
  67. 67.
    Bentley GE (2003) Melatonin receptor density in area X of european starlings is correlated with reproductive state and is unaffected by plasma melatonin concentration. Gen Comp Endocrinol 134:187–192PubMedCrossRefGoogle Scholar
  68. 68.
    Yasuo S, Yoshimura T, Ebihara S, Korf H-W (2009) Melatonin transmits photoperiodic signals through the MT1 melatonin receptor. J Neurosci 29:2885–2889PubMedCrossRefGoogle Scholar
  69. 69.
    Carcangiu V, Mura MC, Vacca GM, Dettori ML, Pazzola M, Daga C et al (2010) Characterization of the melatonin receptor gene MT1 in mouflon (Ovis Gmelini Musimon) and its relationship with reproductive activity. Mol Reprod Dev 77:196PubMedGoogle Scholar
  70. 70.
    Prendergast BJ (2010) MT1 melatonin receptors mediate somatic, behavioral, and reproductive neuroendocrine responses to photoperiod and melatonin in Siberian hamsters (Phodopus sungorus). Endocrinology 151:714–721PubMedCrossRefGoogle Scholar
  71. 71.
    Carcangiu V, Vacca GM, Mura MC, Dettori ML, Pazzola M, Luridiana S et al (2009) Relationship between MTNR1A melatonin receptor gene polymorphism and seasonal reproduction in different goat breeds. Anim Reprod Sci 110:71–78PubMedCrossRefGoogle Scholar
  72. 72.
    Yang WC, Tang KQ, Fu CZ, Riaz H, Zhang Q, Sen Zan L (2014) Melatonin regulates the development and function of bovine Sertoli cells via its receptors MT1 and MT2. Anim Reprod Sci 147:10–16PubMedCrossRefGoogle Scholar
  73. 73.
    El-Raey M, Geshi M, Somfai T, Kaneda M, Hirako M, Abdel-Ghaffar AE et al (2011) Evidence of melatonin synthesis in the cumulus oocyte complexes and its role in enhancing oocyte maturation in vitro in cattle. Mol Reprod Dev 78:250–262PubMedCrossRefGoogle Scholar
  74. 74.
    Nosjean O, Ferro M, Cogé F, Beauverger P, Henlin JM, Lefoulon F et al (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 275:31311–31317PubMedCrossRefGoogle Scholar
  75. 75.
    Ferry G, Hecht S, Berger S, Moulharat N, Coge F, Guillaumet G et al (2010) Old and new inhibitors of quinone reductase 2. Chem Biol Interact 186:103–109PubMedCrossRefGoogle Scholar
  76. 76.
    Boutin JA, Marcheteau E, Hennig P, Moulharat N, Berger S, Delagrange P et al (2008) MT3/QR2 melatonin binding site does not use melatonin as a substrate or a co-substrate. J Pineal Res 45:524–531PubMedCrossRefGoogle Scholar
  77. 77.
    Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML (2016) MT 1 and MT 2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol 56:361–383PubMedCrossRefGoogle Scholar
  78. 78.
    Ayoub MA, Delagrange P, Jockers R (2004) Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties. Mol Pharmacol 66:312–321PubMedCrossRefGoogle Scholar
  79. 79.
    Levoye A, Dam J, Ayoub MA, Guillaume J-L, Couturier C, Delagrange P et al (2006) The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J 25:3012–3023PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Baba K, Benleulmi-Chaachoua A, Journé A-S, Kamal M, Guillaume J-L, Dussaud S et al (2013) Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal 6:ra89PubMedCrossRefGoogle Scholar
  81. 81.
    Kamal M, Gbahou F, Guillaume JL, Daulat AM, Benleulmi-Chaachoua A, Luka M et al (2015) Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers. J Biol Chem 290:11537–11546PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Simonneaux V (2003) Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 55:325–395PubMedCrossRefGoogle Scholar
  83. 83.
    Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK et al (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91–102PubMedCrossRefGoogle Scholar
  84. 84.
    Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E (2005) Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57BL/6 mouse. J Pineal Res 39:113–120PubMedCrossRefGoogle Scholar
  85. 85.
    Alcantara-Contreras S, Baba K, Tosini G (2011) Removal of melatonin receptor type 1 increases intraocular pressure and retinal ganglion cells death in the mouse. Neurosci Lett 494:61–64PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Gianesini C, Hiragaki S, Laurent V, Hicks D, Tosini G (2016) Cone viability is affected by disruption of melatonin receptors signaling. Investig Ophthalmol Vis Sci 57:94–104CrossRefGoogle Scholar
  87. 87.
    Ochoa-Sanchez R, Comai S, Lacoste B, Bambico FR, Dominguez-lopez S, Spadoni G et al (2011) Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand. J Neurosci 31:18439–18452PubMedCrossRefGoogle Scholar
  88. 88.
    Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P et al (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82–88PubMedCrossRefGoogle Scholar
  89. 89.
    Bonnefond A, Clément N, Fawcett K, Yengo L, Vaillant E, Guillaume J-L et al (2012) Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 44:297–301PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Contreras-Alcantara S, Baba K, Tosini G (2010) Removal of melatonin receptor type 1 induces insulin resistance in the mouse. Obesity (Silver Spring) 18:1861–1863CrossRefGoogle Scholar
  91. 91.
    Lardone PJ, Rubio A, Cerrillo I, Gómez-Corvera A, Carrillo-Vico A, Sanchez-Hidalgo M et al (2010) Blocking of melatonin synthesis and MT1 receptor impairs the activation of Jurkat T cells. Cell Mol Life Sci 67:3163–3172PubMedCrossRefGoogle Scholar
  92. 92.
    Lee JS, Cua DJ (2015) Melatonin lulling Th17 cells to sleep. Cell 162:1212–1214PubMedCrossRefGoogle Scholar
  93. 93.
    Wurtman RJ, Axelrod J, Potter LT (1964) The uptake of H3-melatonin in endocrine and nervous tissues and the effects of constant light exposure. J Pharmacol Exp Ther 143:314–318PubMedGoogle Scholar
  94. 94.
    Cohen M, Roselle D, Chabner B, Schmidt TJ, Lippman M (1978) Evidence for a cytoplasmic melatonin receptor. Nature 274:894–895PubMedCrossRefGoogle Scholar
  95. 95.
    Acuña-Castroviejo D, Pablos MI, Menéndez-Peláez A, Reiter RJ (1993) Melatonin receptors in purified cell nuclei of liver. Res Commun Chem Pathol Pharmacol 82:253–256PubMedGoogle Scholar
  96. 96.
    Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat JH et al (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem 269:28531–28534PubMedGoogle Scholar
  97. 97.
    Steinhilber D, Brungs M, Werz O, Wiesenberg I, Danielsson C, Kahlen JP et al (1995) The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes. J Biol Chem 270:7037–7040PubMedCrossRefGoogle Scholar
  98. 98.
    Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C (1995) Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Res 23:327–333PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Escames G, León J, López LC, Acuña-Castroviejo D (2004) Mechanisms of N-methyl-d-aspartate receptor inhibition by melatonin in the rat striatum. J Neuroendocrinol 16:929–935PubMedCrossRefGoogle Scholar
  100. 100.
    García-Navarro A, González-Puga C, Escames G, López LC, López A, López-Cantarero M et al (2007) Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res 43:195–205PubMedCrossRefGoogle Scholar
  101. 101.
    Carrillo-Vico A, García-Pergañeda A, Naji L, Calvo JR, Romero MP, Guerrero JM (2003) Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 60:2272–2278PubMedCrossRefGoogle Scholar
  102. 102.
    Levin ER, Hammes SR (2016) Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 17:783–797PubMedCrossRefGoogle Scholar
  103. 103.
    Ryu CS, Klein K, Zanger UM (2017) Membrane-associated progesterone receptors: promiscuous proteins with pleiotropic functions—focus on interactions with cytochromes P450. Front Pharmacol 8:159PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Rahman F, Christian HC (2007) Non-classical actions of testosterone: an update. Trends Endocrinol Metab 18:371–378PubMedCrossRefGoogle Scholar
  105. 105.
    Thomas P, Converse A, Berg HA (2017) ZIP9, a novel membrane androgen receptor and zinc transporter protein. Gen Comp Endocrinol. doi: 10.1016/j.ygcen.2017.04.016 Google Scholar
  106. 106.
    Balzer I, Hardeland R (1991) Photoperiodism and effects of indoleamines in a unicellular alga, Gonyaulax polyedra. Science 80(253):795–797CrossRefGoogle Scholar
  107. 107.
    Tan DX, Chen LD, Poeggeler B, Manchester L, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:59–60Google Scholar
  108. 108.
    Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129–1146PubMedGoogle Scholar
  109. 109.
    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
  110. 110.
    Manchester LC, Coto-Montes A, Boga JA, Andersen LPH, Zhou Z, Galano A et al (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59:403–419PubMedCrossRefGoogle Scholar
  111. 111.
    Sainz RM, Reiter RJ, Mayo JC, Cabrera J, Tan DX, Qi W et al (2000) Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy. J Reprod Fertil 119:143–149PubMedCrossRefGoogle Scholar
  112. 112.
    García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA 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
  113. 113.
    Mayo JC, Tan DX, Sainz RM, Natarajan M, Lopez-Burillo S, Reiter RJ (2003) Protection against oxidative protein damage induced by metal-catalyzed reaction or alkylperoxyl radicals: comparative effects of melatonin and other antioxidants. Biochim Biophys Acta Gen Subj 1620:139–150CrossRefGoogle Scholar
  114. 114.
    Tan D, Reiter RJ, Chen LD, Poeggeler B, Manchester LC, Barlow-walden LR (1994) Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. Carcinogenesis 15:215–218PubMedCrossRefGoogle Scholar
  115. 115.
    Pappolla MA, Chyan YJ, Poeggeler B, Bozner P, Ghiso J, LeDoux SP et al (1999) Alzheimer beta protein mediated oxidative damage of mitochondrial DNA: prevention by melatonin. J Pineal Res 27:226–229PubMedCrossRefGoogle Scholar
  116. 116.
    Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST et al (1998) A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 253:614–620PubMedCrossRefGoogle Scholar
  117. 117.
    Hardeland R, Balzer I, Poeggeler B, Fuhrberg B, Una H, Behrmann G et al (1995) On the primary functions of melatonin in evolution: mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals. J Pineal Res 18:104–111PubMedCrossRefGoogle Scholar
  118. 118.
    Tan DX, Reiter RJ, Manchester LC, Yan M, El-Sawi M, Sainz RM 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
  119. 119.
    Ressmeyer AR, Mayo JC, Zelosko V, Sainz RM, Tan DX, Poeggeler B et al (2003) Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox Rep 8:205–213PubMedCrossRefGoogle Scholar
  120. 120.
    Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C et al (2005) Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 165:139–149PubMedCrossRefGoogle Scholar
  121. 121.
    Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42:28–42PubMedCrossRefGoogle Scholar
  122. 122.
    Abe M, Reiter RJ, Orhii PB, Hara M, Poeggeler B (1994) Inhibitory effect of melatonin on cataract formation in newborn rats: evidence for an antioxidative role for melatonin. J Pineal Res 17:94–100PubMedCrossRefGoogle Scholar
  123. 123.
    Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Rodriguez C et al (2002) Melatonin regulation of antioxidant enzyme gene expression. Cell Mol Life Sci 59:1706–1713PubMedCrossRefGoogle Scholar
  124. 124.
    Rodriguez-Garcia A, Hevia D, Mayo JC, Gonzalez-Menendez P, Coppo L, Lu J et al (2017) Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells. Redox Biol 12:634–647PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Mayo JC, Tan DX, Sainz RM, Lopez-Burillo S, Reiter RJ (2003) Oxidative damage to catalase induced by peroxyl radicals: functional protection by melatonin and other antioxidants. Free RadicRes 37:543–553CrossRefGoogle Scholar
  126. 126.
    Tan D, Hardeland R, Manchester LC, Poeggeler B, Lopez-Burillo S, Mayo JC et al (2003) Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical. J Pineal Res 34:249–259PubMedCrossRefGoogle Scholar
  127. 127.
    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
  128. 128.
    Il Choi S, Dadakhujaev S, Ryu H, Im Kim T, Kim EK (2011) Melatonin protects against oxidative stress in granular corneal dystrophy type 2 corneal fibroblasts by mechanisms that involve membrane melatonin receptors. J Pineal Res 51:94–103CrossRefGoogle Scholar
  129. 129.
    Wang F, Tian X, Zhang L, Gao C, He C, Fu Y et al (2014) Beneficial effects of melatonin on in vitro bovine embryonic development are mediated by melatonin receptor 1. J Pineal Res 56:333–342PubMedCrossRefGoogle Scholar
  130. 130.
    Sainz RM, Mayo JC, Tan DX, León J, Manchester L, Reiter RJ (2005) Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 63:29–43PubMedCrossRefGoogle Scholar
  131. 131.
    Sainz RM, Mayo JC, Tan DX, Lopez-Burillo S, Natarajan M, Reiter RJ (2003) Antioxidant activity of melatonin in Chinese hamster ovarian cells: changes in cellular proliferation and differentiation. Biochem Biophys Res Commun 302:625–634PubMedCrossRefGoogle Scholar
  132. 132.
    Rodriguez-Garcia A, Mayo JC, Hevia D, Quiros-Gonzalez I, Navarro M, Sainz RM (2013) Phenotypic changes caused by melatonin increased sensitivity of prostate cancer cells to cytokine-induced apoptosis. J Pineal Res 54:33–45PubMedCrossRefGoogle Scholar
  133. 133.
    Mayo JC, Sainz RM, Uria H, Antolin I, Esteban MM, Rodriguez C (1998) Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson’s disease. J Pineal Res 24:179–192PubMedCrossRefGoogle Scholar
  134. 134.
    Watson N, Diamandis T, Gonzales-Portillo C, Reyes S, Borlongan CV (2016) Melatonin as an antioxidant for stroke neuroprotection. Cell Transplant 25:883–891PubMedCrossRefGoogle Scholar
  135. 135.
    O’Neal-Moffitt G, Delic V, Bradshaw PC, Olcese J (2015) Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPP(swe)/PS1 mice. Mol Neurodegener 10:27PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Halliwell B (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol 141:312–322PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Halliwell B, Gutteridge JMC (1985) Free radicals in biology and medicine. doi: 10.1016/0748-5514(85)90140-0 Google Scholar
  138. 138.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13PubMedCrossRefGoogle Scholar
  139. 139.
    Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuña-Castroviejo D, Reiter RJ et al (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
  140. 140.
    Manchester LC, Poeggeler B, Alvares 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
  141. 141.
    Balzer I, Kapp H (2000) Occurrence and comparative physiology of melatonin in evolutionary diverse organisms. In: Vanden Driessche T, Petiau-de Vries GM (eds) Redox state circadian rhythm. Kluwer Academic Publishers, Dordrecht, pp 95–119CrossRefGoogle Scholar
  142. 142.
    Tilden AR, Becker MA, Amma LL, Arciniega J, McGaw AK (1997) Melatonin production in an aerobic photosynthetic bacterium: an evolutionarily early association with darkness. J Pineal Res 22:102–106PubMedCrossRefGoogle Scholar
  143. 143.
    Poeggeler B, Hardeland R (1994) Detection and quantification of melatonin in a dinoflagellate, Gonyaulax polyedra: solutions to the problem of methoxyindole destruction in non-vertebrate material. J Pineal Res 17:1–10PubMedCrossRefGoogle Scholar
  144. 144.
    Dubbels R, Reiter RJJ, Klenke E, Goebel A, Schnakenberg E, Ehlers C et al (1995) Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 18:28–31PubMedCrossRefGoogle Scholar
  145. 145.
    Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R et al (1995) Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 35:627–634PubMedGoogle Scholar
  146. 146.
    Reiter RJ, Tan DX, Rosales-Corral S, Manchester LC (2013) The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini Rev Med Chem 13:373–384PubMedGoogle Scholar
  147. 147.
    Tzameli I (2012) The evolving role of mitochondria in metabolism. Trends Endocrinol Metab 23:417–419PubMedCrossRefGoogle Scholar
  148. 148.
    Nasrallah CM, Horvath TL (2014) Mitochondrial dynamics in the central regulation of metabolism. Nat Rev Endocrinol 10:650–658PubMedCrossRefGoogle Scholar
  149. 149.
    Trotta AP, Chipuk JE (2017) Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci 74:1–19CrossRefGoogle Scholar
  150. 150.
    Galluzzi L, Kepp O, Kroemer G (2016) Mitochondrial regulation of cell death: a phylogenetically conserved control. Microb Cell 3:101–108PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Drake LE, Springer MZ, Poole LP, Kim CJ, Macleod KF (2017) Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol. doi: 10.1016/j.semcancer.2017.04.008 PubMedGoogle Scholar
  152. 152.
    Galluzzi L, Bravo-San Pedro JM, Demaria S, Formenti SC, Kroemer G (2016) Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol 14:247–258PubMedCrossRefGoogle Scholar
  153. 153.
    Calabrese G, Morgan B, Riemer J (2017) Mitochondrial glutathione: regulation and functions. Antioxid Redox Signal. doi: 10.1089/ars.2017.7121
  154. 154.
    Kezic A, Spasojevic I, Lezaic V, Bajcetic M (2016) Mitochondria-targeted antioxidants: future perspectives in kidney ischemia-reperfusion injury. Oxid Med Cell Longev 2016:2950503PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Yang Y, Karakhanova S, Hartwig W, D’Haese JG, Philippov PP, Werner J et al (2016) Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol 231:2570–2581PubMedCrossRefGoogle Scholar
  156. 156.
    Silva FSG, Simoes RF, Couto R, Oliveira PJ (2016) Targeting mitochondria in cardiovascular diseases. Curr Pharm Des 22:5698–5717PubMedCrossRefGoogle Scholar
  157. 157.
    Coon SL, Klein DC (2006) Evolution of arylalkylamine N-acetyltransferase: emergence and divergence. Mol Cell Endocrinol 252:2–10PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Tan DX, Hardeland R, Back K, Manchester LC, Alatorre-Jimenez MA, Reiter RJ (2016) On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species. J Pineal Res 61:27–40PubMedCrossRefGoogle Scholar
  159. 159.
    Byeon Y, Lee HY, Choi DW, Back K (2015) Chloroplast-encoded serotonin N-acetyltransferase in the red alga Pyropia yezoensis: gene transition to the nucleus from chloroplasts. J Exp Bot 66:709–717PubMedCrossRefGoogle Scholar
  160. 160.
    Martín M, Macías M, Escames G, León J, Acuña-Castroviejo D (2000) Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress. FASEB J 14:1677–1679PubMedGoogle Scholar
  161. 161.
    Martín M, Macías M, Escames G, Reiter RJ, Agapito MT, Ortiz GG 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
  162. 162.
    León J, Acuña-Castroviejo D, Escames G, Tan DX, Reiter RJ (2005) Melatonin mitigates mitochondrial malfunction. J Pineal Res 38:1–9PubMedCrossRefGoogle Scholar
  163. 163.
    Jou MJ, Peng TI, Yu PZ, Bin Jou S, Reiter RJ, Chen JY et al (2007) Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis. J Pineal Res 43:389–403PubMedCrossRefGoogle Scholar
  164. 164.
    Hardeland R, Coto Montes A, Poeggeler B (2003) Circadian rhythms, oxidative stress, and antioxidative defense mechanisms. Chronobiol Int 20:921–962PubMedCrossRefGoogle Scholar
  165. 165.
    Leon J, Acuña-Castroviejo D, Sainz RM, Mayo JC, Tan D-XX, Reiter RJ (2004) Melatonin and mitochondrial function. Life Sci 75:765–790PubMedCrossRefGoogle Scholar
  166. 166.
    Mayo JC, Sainz RM, Tan D-X, Antolín I, Rodríguez C, Reiter RJ (2005) Melatonin and Parkinson’s disease. Endocrine 27:169–178PubMedCrossRefGoogle Scholar
  167. 167.
    Antolín I, Mayo JC, Sainz RM, del Brío MA, Herrera F, Martín V et al (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943:163–173PubMedCrossRefGoogle Scholar
  168. 168.
    Tapias V, Escames G, López LC, López A, Camacho E, Carrión MD et al (2009) Melatonin and its brain metabolite N1-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in Parkinsonian mice. J Neurosci Res 87:3002–3010PubMedCrossRefGoogle Scholar
  169. 169.
    Shida C, Castrucci AML, Lamy-Freund MT (1994) High melatonin solubility in aqueous medium. J Pineal Res 16:198–201PubMedCrossRefGoogle Scholar
  170. 170.
    Costa EJX, Lopes RH, Lamy-Freund MT (1995) Permeability of pure lipid bilayers to melatonin. J Pineal Res 19:123–126PubMedCrossRefGoogle Scholar
  171. 171.
    Costa EJX, Shida CS, Biaggi MH, Ito AS, Lamy-Freund MT (1997) How melatonin interacts with lipid bilayers: a study by fluorescence and ESR spectroscopies. FEBS Lett 416:103–106PubMedCrossRefGoogle Scholar
  172. 172.
    Saija A, Tomaino A, Trombetta D, Pellegrino ML, Tita B, Caruso S et al (2002) Interaction of melatonin with model membranes and possible implications in its photoprotective activity. Eur J Pharm Biopharm 53:209–215PubMedCrossRefGoogle Scholar
  173. 173.
    Severcan F, Sahin I, Kazanci N (2005) Melatonin strongly interacts with zwitterionic model membranes-evidence from Fourier transform infrared spectroscopy and differential scanning calorimetry. Biochim Biophys Acta Biomembr 1668:215–222CrossRefGoogle Scholar
  174. 174.
    Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C et al (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227PubMedCrossRefGoogle Scholar
  175. 175.
    Melchiorri D, Reiter RJ, Sewerynek E, Chen LD, Nisticó G (1995) Melatonin reduces kainate-induced lipid peroxidation in homogenates of different brain regions. FASEB J 9:1205–1210PubMedGoogle Scholar
  176. 176.
    García JJ, Reiter RJ, Guerrero JM, Escames G, Yu BP, Oh CS et al (1997) Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett 408:297–300PubMedCrossRefGoogle Scholar
  177. 177.
    van Ginkel G, van Langen H, Levine YK (1989) The membrane fluidity concept revisited by polarized fluorescence spectroscopy on different model membranes containing unsaturated lipids and sterols. Biochimie 71:23–32PubMedCrossRefGoogle Scholar
  178. 178.
    Dies H, Cheung B, Tang J, Rheinstädter MC (2015) The organization of melatonin in lipid membranes. Biochim Biophys Acta Biomembr 1848:1032–1040CrossRefGoogle Scholar
  179. 179.
    Yu H, Dickson EJ, Jung S-R, Koh D-S, Hille B (2016) High membrane permeability for melatonin. J Gen Physiol 147:63–76PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ (2003) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407–1426PubMedCrossRefGoogle Scholar
  181. 181.
    Wenzel U, Nickel A, Daniel H (2005) Melatonin potentiates flavone-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products. Int J Cancer 116:236–242PubMedCrossRefGoogle Scholar
  182. 182.
    Hevia D, Sainz RM, Blanco D, Quirós I, Tan DX, Rodríguez C et al (2008) Melatonin uptake in prostate cancer cells: intracellular transport versus simple passive diffusion. J Pineal Res 45:247–257PubMedCrossRefGoogle Scholar
  183. 183.
    Hevia D, González-Menéndez P, Quiros-González I, Miar A, Rodríguez-García A, Tan DX et al (2015) Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer. J Pineal Res 58:234–250PubMedCrossRefGoogle Scholar
  184. 184.
    Hevia D, Rodriguez-Garcia A, Alonso-Gervós M, Quirós-González I, Cimadevilla HM, Gómez-Cordovés C et al (2011) Cell volume and geometric parameters determination in living cells using confocal microscopy and 3D reconstruction: protocol exchange. Protoc Exch. doi: 10.1038/protex.2011.272
  185. 185.
    Deng D, Sun P, Yan C, Ke M, Jiang X, Xiong L et al (2015) Molecular basis of ligand recognition and transport by glucose transporters. Nature 526:391–396PubMedCrossRefGoogle Scholar
  186. 186.
    Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL et al (2008) Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. Cell 132:1039–1048PubMedCrossRefGoogle Scholar
  187. 187.
    Huo X, Wang C, Yu Z, Peng Y, Wang S, Feng S et al (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
  188. 188.
    Mayo JC, Sainz RM, González-Menéndez P, Cepas V, Tan D-X, Reiter RJ (2017) Melatonin and sirtuins: a “not-so unexpected” relationship. J Pineal Res 62:e12391CrossRefGoogle Scholar
  189. 189.
    Radogna F, Cristofanon S, Paternoster L, D’Alessio M, De Nicola M, Cerella C et al (2008) Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2. J Pineal Res 44:316–325PubMedCrossRefGoogle Scholar
  190. 190.
    Liesa M, Qiu W, Shirihai OS (2012) Mitochondrial ABC transporters function: the role of ABCB10 (ABC-me) as a novel player in cellular handling of reactive oxygen species. Biochim Biophys Acta Mol Cell Res 1823:1945–1957CrossRefGoogle Scholar
  191. 191.
    Palmieri F (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med 34:465–484PubMedCrossRefGoogle Scholar
  192. 192.
    Kc S (2005) Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 19:1657–1667PubMedCrossRefGoogle Scholar
  193. 193.
    Sage JM, Carruthers A (2014) Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex. AJP Cell Physiol 306:C910–C917CrossRefGoogle Scholar
  194. 194.
    Lee YC, Huang HY, Chang CJ, Cheng CH, Chen YT (2010) Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: mechanistic insight into arterial tortuosity syndrome. Hum Mol Genet 19:3721–3733PubMedCrossRefGoogle Scholar
  195. 195.
    Muñoz-Montesino C, Roa FJ, Peña E, González M, Sotomayor K, Inostroza E et al (2014) Mitochondrial ascorbic acid transport is mediated by a low-affinity form of the sodium-coupled ascorbic acid transporter-2. Free Radic Biol Med 70:241–254PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Juan C. Mayo
    • 1
    • 2
    Email author
  • Rosa M. Sainz
    • 1
    • 2
  • Pedro González-Menéndez
    • 1
    • 2
  • David Hevia
    • 1
    • 2
  • Rafael Cernuda-Cernuda
    • 1
  1. 1.Departamento de Morfología y Biología Celular, Facultad de MedicinaUniversidad de OviedoOviedoSpain
  2. 2.Instituto Universitario Oncológico del Principado de AsturiasUniversidad de OviedoOviedoSpain

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