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Review

Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment

, , & ORCID Icon
Pages 359-378 | Received 23 Nov 2019, Accepted 27 Feb 2020, Published online: 02 Mar 2020

References

  • Kaarniranta K, Salminen A, Haapasalo A, et al. Age-related macular degeneration (AMD): Alzheimer’s disease in the eye? J Alzheimers Dis. 2011;24(4):615–631.
  • Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–572.
  • Coleman HR, Chan -C-C, Ferris III FL, et al. Age-related macular degeneration. Lancet. 2008;372(9652):1835–1845.
  • Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358(24):2606–2617.
  • Klein R, Klein BE, Jensen SC, et al. Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology. 1999;106(6):1056–1065.
  • Schachat AP, Hyman L, Leske MC, et al. Features of age-related macular degeneration in a black population. Arch Ophtalmol. 1995;113(6):728–735.
  • Mukesh BN, Dimitrov PN, Leikin S, et al. Five-year incidence of age-related maculopathy: the visual impairment project. Ophthalmology. 2004;111(6):1176–1182.
  • Provis JM. Development of the primate retinal vasculature. Prog Retin Eye Res. 2001 Nov;20(6):799–821.
  • Pournaras CJ, Rungger-Brandle E, Riva CE, et al. Regulation of retinal blood flow in health and disease. Prog Retin Eye Res. 2008 May;27(3):284–330.
  • Steuer H, Jaworski A, Elger B, et al. Functional characterization and comparison of the outer blood-retina barrier and the blood-brain barrier. Invest Ophthalmol Vis Sci. 2005 Mar;46(3):1047–1053.
  • Rizzolo LJ. Polarity and the development of the outer blood-retinal barrier. Histol Histopathol. 1997 Oct;12(4):1057–1067.
  • Okano K, Maeda A, Chen Y, et al. Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light‐induced damage. J Neurochem. 2012;121(1):146–156.
  • Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33(4):295–317.
  • Rickman CB, Farsiu S, Toth CA, et al. Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest Ophthalmol Vis Sci. 2013;54(14):ORSF68–ORSF80.
  • Gehrs KM, Anderson DH, Johnson LV, et al. Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38(7):450–471.
  • Wang Y, Wang V, Chan C. The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment. Eye. 2011;25(2):127.
  • Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292–2299.
  • Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175–1183.
  • Group A-REDSR. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8 Arch Ophthalmol. 2001;119(10):1417.
  • Reiter RJ, Tan D-X, Fuentes-Broto L. Melatonin: a multitasking molecule. In: Progress in brain research. Vol. 181. Prog Brain Res. 2010;181:127–151.
  • Hosseinzadeh A, Kamrava SK, Joghataei MT, et al. Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res. 2016;61(4):411–425.
  • Dehdashtian E, Mehrzadi S, Yousefi B, et al. Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sci. 2018;193:20–33.
  • Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, et al. Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci. 2018;201:17–29.
  • Zhao D, Yu Y, Shen Y, et al. Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol (Lausanne). 2019;10:249.
  • Tan DX, Hardeland R, Back K, et al. On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species. J Pineal Res. 2016 Aug;61(1):27–40.
  • Reiter RJ, Tan DX, Kim SJ, et al. Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow–Robin perivascular spaces. Brain Struct Funct. 2014 Nov 01;219(6):1873–1887.
  • Reiter RJ, Tan D-X, Manchester L, et al. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci. 2007;52:11-28.
  • Sakamoto K, Liu C, Tosini G. Circadian rhythms in the retina of rats with photoreceptor degeneration. J Neurochem. 2004;90(4):1019–1024.
  • Cahill GM, Besharse JC. Circadian clock functions localized in Xenopus retinal photoreceptors. Neuron. 1993;10(4):573–577.
  • Liu C, Fukuhara C, Wessel JH, et al. Localization of Aa-nat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection. Cell Tissue Res. 2004;315(2):197–201.
  • Lundmark PO, Pandi-Perumal SR, Srinivasan V, et al. Role of melatonin in the eye and ocular dysfunctions. Vis Neurosci. 2006;23(6):853–862.
  • Meyer P, Pache M, Loeffler K, et al. Melatonin MT-1-receptor immunoreactivity in the human eye. Br J Ophthalmol. 2002;86(9):1053–1057.
  • Siu A, Ortiz G, Benitez-King G, et al. Effects of melatonin on the nitric oxide treated retina. Br J Ophthalmol. 2004;88(8):1078–1081.
  • Alarma-Estrany P, Pintor J. Melatonin receptors in the eye: location, second messengers and role in ocular physiology. Pharmacol Ther. 2007;113(3):507–522.
  • Rosen R, Hu D-N, Perez V, et al. Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients. Mol Vis. 2009;15:1673.
  • Lv X, Liu S, Cao Z, et al. Correlation between serum melatonin and aMT6S level for age-related macular degeneration patients. Eur Rev Med Pharmacol Sci. 2016;20(20):4196–4201.
  • Yi C, Pan X, Yan H, et al. Effects of melatonin in age‐related macular degeneration. Ann NY Acad Sci. 2005;1057(1):384–392.
  • Rambold AS, Lippincott-Schwartz J. Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle. 2011;10(23):4032–4038.
  • Norberg E, Orrenius S, Zhivotovsky B. Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun. 2010;396(1):95–100.
  • Mokranjac D, Neupert W. Thirty years of protein translocation into mitochondria: unexpectedly complex and still puzzling. Biochim Biophys Acta-Mol Cell Res. 2009;1793(1):33–41.
  • Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305(5684):626–629.
  • Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281(5381):1309.
  • Reynafarje BD, Ferreira J. Oxidative phosphorylation: kinetic and thermodynamic correlation between electron flow, proton translocation, oxygen consumption and ATP synthesis under close to in vivo concentrations of oxygen. Int J Med Sci. 2008;5(3):143.
  • Mazat JP, Ransac S, Heiske M, et al. Mitochondrial energetic metabolism—some general principles. IUBMB Life. 2013;65(3):171–179.
  • Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407.
  • Terluk MR, Kapphahn RJ, Soukup LM, et al. Investigating mitochondria as a target for treating age-related macular degeneration. J Neurosci. 2015;35(18):7304–7311.
  • Feher J, Kovacs I, Artico M, et al. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging. 2006;27(7):983–993.
  • Nordgaard CL, Berg KM, Kapphahn RJ, et al. Proteomics of the retinal pigment epithelium reveals altered protein expression at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006;47(3):815–822.
  • Nordgaard CL, Karunadharma PP, Feng X, et al. Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49(7):2848–2855.
  • Kriegenburg F, Ellgaard L, Hartmann‐Petersen R. Molecular chaperones in targeting misfolded proteins for ubiquitin‐dependent degradation. Febs J. 2012;279(4):532–542.
  • Kinnunen K, Petrovski G, Moe MC, et al. Molecular mechanisms of retinal pigment epithelium damage and development of age‐related macular degeneration. Acta Ophthalmol. 2012;90(4):299–309.
  • Verghese J, Abrams J, Wang Y, et al. Biology of the heat shock response and protein chaperones: budding yeast (Saccharomyces cerevisiae) as a model system. Microbiol Mol Biol Rev. 2012;76(2):115–158.
  • Voos W, Röttgers K. Molecular chaperones as essential mediators of mitochondrial biogenesis. Biochim Biophys Acta-Mol Cell Res. 2002;1592(1):51–62.
  • Kaufman BA, Kolesar JE, Perlman PS, et al. A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol. 2003;163(3):457–461.
  • Kaufman BA, Newman SM, Hallberg RL, et al. In organello formaldehyde crosslinking of proteins to mtDNA: identification of bifunctional proteins. Proc Nat Acad Sci. 2000;97(14):7772–7777.
  • Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454.
  • Karunadharma PP, Nordgaard CL, Olsen TW, et al. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5470–5479.
  • Liang F-Q, Godley BF. Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res. 2003;76(4):397–403.
  • Fletcher A. Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration. Ophthalmic Res. 2010;44(3):191–198.
  • Wu J, Seregard S, Algvere PV. Photochemical damage of the retina. Surv Ophthalmol. 2006;51(5):461–481.
  • Godley BF, Shamsi FA, Liang F-Q, et al. Blue light induces mitochondrial DNA damage and free radical production in epithelial cells. J Biol Chem. 2005;280(22):21061–21066.
  • Wright AF, Jacobson SG, Cideciyan AV, et al. Lifespan and mitochondrial control of neurodegeneration. Nat Genet. 2004;36(11):1153.
  • Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10(1):9.
  • Aguirre E, López-Bernardo E, Cadenas S. Functional evidence for nitric oxide production by skeletal-muscle mitochondria from lipopolysaccharide-treated mice. Mitochondrion. 2012;12(1):126–131.
  • Ghafourifar P, Richter C. Nitric oxide synthase activity in mitochondria. FEBS Lett. 1997;418(3):291–296.
  • Cardinali DP, Pagano ES, Scacchi Bernasconi PA, et al. Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav. 2013 Feb 01;63(2):322–330.
  • Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends Pharmacol Sci. 2005 Apr;26(4):190–195.
  • Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
  • Lismont C, Nordgren M, Van Veldhoven PP, et al. Redox interplay between mitochondria and peroxisomes. Front Cell Dev Biol. 2015;3:35.
  • Van Houten B, Woshner V, Santos JH. Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst). 2006;5(2):145–152.
  • Wei Y-H, Lee H-C. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med. 2002;227(9):671–682.
  • Wei Y-H, Lu C-Y, Wei C-Y, et al. Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. Chin J Physiol. 2001;44(1):1–12.
  • Canter JA, Olson LM, Spencer K, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PloS One. 2008;3(5):e2091.
  • Gotoh N, Nakanishi H, Hayashi H, et al. ARMS2 (LOC387715) variants in Japanese patients with exudative age-related macular degeneration and polypoidal choroidal vasculopathy. Am J Ophthalmol. 2009;147(6):1037–1041. e2.
  • Zareparsi S, Branham KE, Li M, et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet. 2005;77(1):149–153.
  • Souied EH, Leveziel N, Richard F, et al. Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis. 2005;11(131–32):1135–1140.
  • Edwards AO, Ritter R, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–424.
  • Grassi MA, Fingert JH, Scheetz TE, et al. Ethnic variation in AMD‐associated complement factor H polymorphism pTyr402His. Hum Mutat. 2006;27(9):921–925.
  • Seitsonen S, Lemmela S, Holopainen J, et al. Analysis of variants in the complement factor H, the elongation of very long chain fatty acids-like 4 and the hemicentin 1 genes of age-related macular degeneration in the Finnish population. Mol Vis. 2006;12:796–801.
  • Martin S, Bodek E, Geng L, et al. Complement factor H (CFH) expression in mammalian retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2008;49(13):206.
  • Chen M, Forrester JV, Xu H. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res. 2007 Apr 01;84(4):635–645.
  • Ding X, Patel M, Chan -C-C. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2009;28(1):1–18.
  • Geerlings MJ, de Jong EK, den Hollander AI. The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment. Mol Immunol. 2017 Apr 01;84:65–76.
  • Ferrington DA, Kapphahn RJ, Leary MM, et al. Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration. Exp Eye Res. 2016;145(145):269–277.
  • Xu Y, Guan N, Xu J, et al. Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population. Mol Vis. 2008;14:1373.
  • Kanda A, Chen W, Othman M, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Nat Acad Sci. 2007;104(41):16227–16232.
  • Gibbs D, Yang Z, Constantine R, et al. Further mapping of 10q26 supports strong association of HTRA1 polymorphisms with age-related macular degeneration. Vision Res. 2008;48(5):685–689.
  • Ng TK, Liang XY, Lai TY, et al. HTRA1 promoter variant differentiates polypoidal choroidal vasculopathy from exudative age-related macular degeneration. Sci Rep. 2016;6:28639.
  • Chien J, Staub J, Hu S-I, et al. A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene. 2004;23(8):1636.
  • Chien J, Aletti G, Baldi A, et al. Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. J Clin Invest. 2006;116(7):1994–2004.
  • He X, Khurana A, Maguire JL, et al. HtrA1 sensitizes ovarian cancer cells to cisplatin‐induced cytotoxicity by targeting XIAP for degradation. Int J Cancer. 2012;130(5):1029–1035.
  • Yu T, Chen C-Z, Xing Y-Q. Inhibition of cell proliferation, migration and apoptosis in blue-light illuminated human retinal pigment epithelium cells by down-regulation of HtrA1. Int J Ophthalmol. 2017;10(4):524.
  • Ng TK, Liang XY, Pang CP. HTRA1 in age-related macular degeneration. Asia-Pac J Ophthalmol. 2012;1(1):51–63.
  • Kerrison JB, Howell N, Miller NR, et al. Leber hereditary optic neuropathy: electron microscopy and molecular genetic analysis of a case. Ophthalmology. 1995;102(10):1509–1516.
  • Wong LJC. Pathogenic mitochondrial DNA mutations in protein‐coding genes. Muscle Nerve. 2007;36(3):279–293.
  • Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6(5):389–402.
  • Jarrett SG, Lin H, Godley BF, et al. Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res. 2008;27(6):596–607.
  • Jarrett SG, Lewin AS, Boulton ME. The importance of mitochondria in age-related and inherited eye disorders. Ophthalmic Res. 2010;44(3):179–190.
  • Udar N, Atilano SR, Memarzadeh M, et al. Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50(6):2966–2974.
  • SanGiovanni JP, Arking DE, Iyengar SK, et al. Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PloS One. 2009;4(5):e5508.
  • Jones MM, Manwaring N, Wang JJ, et al. Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophtalmol. 2007;125(9):1235–1240.
  • Lin H, Xu H, Liang F-Q, et al. Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(6):3521–3529.
  • Kerenyi N, Sotonyi P, Somogyi E. Localizing acethyl-serotonin transferase by electron microscopy. Histochemistry. 1975;46(1):77–80.
  • Suofu Y, Li W, Jean-Alphonse FG, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Nat Acad Sci. 2017;114(38):E7997–E8006.
  • Tan D-X, Manchester L, Qin L, et al. Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci. 2016;17(12):2124.
  • Huo X, Wang C, Yu Z, et al. Human transporters, PEPT 1/2, facilitate melatonin transportation into mitochondria of cancer cells: an implication of the therapeutic potential. J Pineal Res. 2017;62(4):e12390.
  • Semak I, Korik E, Antonova M, et al. Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes. J Pineal Res. 2008;45(4):515–523.
  • Hardeland R, Tan DX, Reiter RJ. Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res. 2009;47(2):109–126.
  • Tan D-X, Reiter RJ. Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res. 2019;2(1):44–66.
  • Tan D-X, Manchester L, Esteban-Zubero E, et al. Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules. 2015;20(10):18886–18906.
  • Semak I, Naumova M, Korik E, et al. A novel metabolic pathway of melatonin: oxidation by cytochrome C. Biochemistry. 2005;44(26):9300–9307.
  • Amara CE, Shankland EG, Jubrias SA, et al. Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc Nat Acad Sci. 2007;104(3):1057–1062.
  • Manchester LC, Coto‐Montes A, Boga JA, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403–419.
  • Carretero M, Escames G, López LC, et al. Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res. 2009 Sep 01;47(2):192–200.
  • Lacza Z, Puskar M, Figueroa JP, et al. Mitochondrial nitric oxide synthase is constitutively active and is functionally upregulated in hypoxia. Free Radic Biol Med. 2001 Dec 15;31(12):1609–1615.
  • Hosseinzadeh A, Kamrava SK, Joghataei MT, et al. Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res. 2016;61:411–425.
  • Escames G, León J, MacÍAs M, et al. Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. Faseb J. 2003 May 01;17(8):932–934.
  • Reiter RJ, Mayo JC, Tan DX, et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61:253–278.
  • Hosseinzadeh A, Kamrava S, Moore B, et al. Molecular aspects of melatonin treatment in tinnitus: a review. Curr Drug Targets. 2019;20:1112–1128.
  • Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, et al. Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis. Expert Opin Ther Targets. 2018;22(12):1049–1061.
  • Reiter RJ, Rosales-Corral S, Tan DX, et al. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci. 2017;74(21):3863–3881.
  • Martin M, Macias M, Escames G, et al. 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. 2000;28(4):242–248.
  • Reiter R, Tan D, Rosales-Corral S, et al. Melatonin mitigates mitochondrial meltdown: interactions with SIRT3. Int J Mol Sci. 2018;19(8):2439.
  • Torrens-Mas M, Oliver J, Roca P, et al. SIRT3: oncogene and tumor suppressor in cancer. Cancers (Basel). 2017;9(7):90.
  • Mayo JC, Sainz RM, González Menéndez P, et al. Melatonin and sirtuins: a “not-so unexpected” relationship. J Pineal Res. 2017 Mar 01;62(2):e12391.
  • Jou MJ, Peng TI, Yu PZ, et al. Melatonin protects against common deletion of mitochondrial DNA‐augmented mitochondrial oxidative stress and apoptosis. J Pineal Res. 2007;43(4):389–403.
  • Xu SC, He MD, Lu YH, et al. Nickel exposure induces oxidative damage to mitochondrial DNA in Neuro2a cells: the neuroprotective roles of melatonin. J Pineal Res. 2011;51(4):426–433.
  • Yan G, Yu L, Jiang S, et al. Melatonin antagonizes oxidative stress-induced mitochondrial dysfunction in retinal pigmented epithelium cells via melatonin receptor 1 (MT1). J Toxicol Sci. 2018;43(11):659–669.
  • Liang F-Q, Green L, Wang C, et al. Melatonin protects human retinal pigment epithelial (RPE) cells against oxidative stress. Exp Eye Res. 2004 June 01;78(6):1069–1075.
  • Fu Y, Tang M, Fan Y, et al. Anti-apoptotic effects of melatonin in retinal pigment epithelial cells. Front Biosci. 2012;17(4):1461–1468.
  • Sripathi SR, Prigge CL, Elledge B, et al. Melatonin modulates prohibitin and cytoskeleton in the retinal pigment epithelium. Int J Sci Eng Res. 2017;8(7):502–506.
  • Sato T, Takeuchi M, Karasawa Y, et al. Intraocular inflammatory cytokines in patients with neovascular age-related macular degeneration before and after initiation of intravitreal injection of anti-VEGF inhibitor. Sci Rep. 2018 Jan 18;8(1):1098.
  • Miceli MV, Jazwinski SM. Nuclear gene expression changes due to mitochondrial dysfunction in ARPE-19 cells: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2005;46(5):1765–1773.
  • Kauppinen A, Paterno JJ, Blasiak J, et al. Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci. 2016;73(9):1765–1786.
  • Johnson PT, Lewis GP, Talaga KC, et al. Drusen-associated degeneration in the retina. Invest Ophthalmol Vis Sci. 2003;44(10):4481–4488.
  • Bhutto IA, McLeod DS, Jing T, et al. Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br J Ophthalmol. 2016;100(5):720–726.
  • Weismann D, Hartvigsen K, Lauer N, et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011;478(7367):76.
  • Toomey CB, Kelly U, Saban DR, et al. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Nat Acad Sci. 2015;112(23):E3040–E3049.
  • Calaza KC, Kam JH, Hogg C, et al. Mitochondrial decline precedes phenotype development in the complement factor H mouse model of retinal degeneration but can be corrected by near infrared light. Neurobiol Aging. 2015 Oct 01;36(10):2869–2876.
  • Pujol-Lereis LM, Schäfer N, Kuhn LB, et al. Interrelation between oxidative stress and complement activation in models of age-related macular degeneration. Adv Exp Med Biol;2016;854:87–93.
  • Gao J, Liu RT, Cao S, et al. NLRP3 inflammasome: activation and regulation in age-related macular degeneration. Mediators Inflamm. 2015;2015:690243.
  • Yang D, Elner SG, Bian Z-M, et al. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res. 2007 Oct 01;85(4):462–472.
  • Damico FM, Gasparin F, Scolari MR, et al. New approaches and potential treatments for dry age-related macular degeneration. Arq Bras Oftalmol. 2012;75(1):71–76.
  • Carrillo-Vico A, Garcia-Perganeda A, Naji L, et al. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci. 2003;60(10):2272–2278.
  • Reiter RJ, Calvo JR, Karbownik M, et al. Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci. 2000;917(1):376–386.
  • Hu ZP, Fang XL, Fang N, et al. Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR 4/NF‐κB system in high‐fat‐fed rabbits. J Pineal Res. 2013;55(4):388–398.
  • Maldonado M, García‐Moreno H, González‐Yanes C, et al. Possible involvement of the inhibition of NF‐κB factor in anti‐inflammatory actions that melatonin exerts on mast cells. J Cell Biochem. 2016;117(8):1926–1933.
  • Kang JC, Ahn M, Kim YS, et al. Melatonin ameliorates autoimmune encephalomyelitis through suppression of intercellular adhesion molecule-1. J Vet Sci. 2001;2(2):85–90.
  • Fernández-Gil B, Moneim AEA, Ortiz F, et al. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One. 2017;12:4.
  • Zhang Y, Li X, Grailer JJ, et al. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. J Pineal Res. 2016;60(4):405–414.
  • Ortiz F, Acuña‐Castroviejo D, Doerrier C, et al. Melatonin blunts the mitochondrial/NLRP 3 connection and protects against radiation‐induced oral mucositis. J Pineal Res. 2015;58(1):34–49.
  • García JA, Volt H, Venegas C, et al. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. Faseb J. 2015;29(9):3863–3875.
  • Laurent V, Sengupta A, Sánchez-Bretaño A, et al. Melatonin signaling affects the timing in the daily rhythm of phagocytic activity by the retinal pigment epithelium. Exp Eye Res. 2017 Dec 01;165:90–95.
  • Xie M, Hu A, Luo Y, et al. Interleukin-4 and melatonin ameliorate high glucose and interleukin-1β stimulated inflammatory reaction in human retinal endothelial cells and retinal pigment epithelial cells. Mol Vis. 2014;20:921.
  • Xu Y, Lu X, Hu Y, et al. Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF‐1α‐VEGF pathway in oxygen‐induced retinopathy mice. J Pineal Res. 2018;64(4):e12473.
  • Jiang T, Chang Q, Cai J, et al. Protective effects of melatonin on retinal inflammation and oxidative stress in experimental diabetic retinopathy. Oxid Med Cell Longev. 2016;2016:3528274.
  • Zhu B, Ma AQ, Yang L, et al. Atorvastatin attenuates bleomycin-induced pulmonary fibrosis via suppressing iNOS expression and the CTGF (CCN2)/ERK signaling pathway. Int J Mol Sci. 2013 Dec 16;14(12):24476–24491.
  • Boga JA, Caballero B, Potes Y, et al. Therapeutic potential of melatonin related to its role as an autophagy regulator: a review. J Pineal Res. 2019;66(1):e12534.
  • Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3–12.
  • Frudd K, Burgoyne T, Burgoyne JR. Oxidation of Atg3 and Atg7 mediates inhibition of autophagy. Nat Commun. 2018;9(1):95.
  • Liu R, Zhi X, Zhong Q. ATG14 controls SNARE-mediated autophagosome fusion with a lysosome. Autophagy. 2015;11(5):847–849.
  • Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014 Jun;16(6):495–501.
  • He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.
  • Alers S, Loffler AS, Wesselborg S, et al. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012 Jan;32(1):2–11.
  • Jawhari S, Ratinaud MH, Verdier M. Glioblastoma, hypoxia and autophagy: a survival-prone ‘menage-a-trois’. Cell Death Dis. 2016 Oct 27;7(10):e2434.
  • Higgins G, Coughlan M. Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br J Pharmacol. 2014;171(8):1917–1942.
  • Saito T, Sadoshima J. Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart. Circ Res. 2015;116(8):1477–1490.
  • Liu L, Sakakibara K, Chen Q, et al. Receptor-mediated mitophagy in yeast and mammalian systems. Cell Res. 2014 Jul;24(7):787–795.
  • Westphal D, Kluck R, Dewson G. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ. 2014;21(2):196.
  • Montero J, Letai A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 2018;25(1):56.
  • Gillies LA, Kuwana T. Apoptosis regulation at the mitochondrial outer membrane. J Cell Biochem. 2014;115(4):632–640.
  • Cai B, Chang S, Becker EB, et al. p38 MAP kinase mediates apoptosis through phosphorylation of Bimel at Ser65. J Biol Chem. 2006;281:25215–25222.
  • Zhuang S, Schnellmann RG. A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther. 2006;319(3):991–997.
  • Lartigue L, Kushnareva Y, Seong Y, et al. Caspase-independent mitochondrial cell death results from loss of respiration, not cytotoxic protein release. Mol Biol Cell. 2009;20(23):4871–4884.
  • Golestaneh N, Chu Y, Xiao -Y-Y, et al. Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Cell Death Dis. 2017;8(1):e2537.
  • Chen Y, Sawada O, Kohno H, et al. Autophagy protects the retina from light-induced degeneration. J Biol Chem. 2013;jbc(M112):439935.
  • Yao J, Jia L, Khan N, et al. Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy. 2015;11(6):939–953.
  • Youle RJ, Van Der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337(6098):1062–1065.
  • Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007;143(3):463–472. e2.
  • Hyttinen JM, Petrovski G, Salminen A, et al. 5′-Adenosine monophosphate-activated protein kinase–mammalian target of rapamycin axis as therapeutic target for age-related macular degeneration. Rejuvenation Res. 2011;14(6):651–660.
  • Mitter SK, Song C, Qi X, et al. Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy. 2014;10(11):1989–2005.
  • Ryhänen T, Hyttinen JM, Kopitz J, et al. Crosstalk between Hsp70 molecular chaperone, lysosomes and proteasomes in autophagy‐mediated proteolysis in human retinal pigment epithelial cells. J Cell Mol Med. 2009;13(9b):3616–3631.
  • Lim SC, Tajika M, Shimura M, et al. Loss of the mitochondrial fatty acid β-oxidation protein medium-chain acyl-coenzyme a dehydrogenase disrupts oxidative phosphorylation protein complex stability and function. Sci Rep. 2018;8(1):153.
  • Bergmann M, Schutt F, Holz F, et al. Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration. Faseb J. 2004;18(3):562–564.
  • Yang P, Peairs JJ, Tano R, et al. Caspase-8–mediated apoptosis in human RPE cells. Invest Ophthalmol Vis Sci. 2007;48(7):3341–3349.
  • Zhang N, Peairs JJ, Yang P, et al. The importance of Bcl-xL in the survival of human RPE cells. Invest Ophthalmol Vis Sci. 2007;48(8):3846–3853.
  • Bhattacharya S, Chaum E, Johnson DA, et al. Age-related susceptibility to apoptosis in human retinal pigment epithelial cells is triggered by disruption of p53–Mdm2 association. Invest Ophthalmol Vis Sci. 2012;53(13):8350–8366.
  • Dunaief JL, Dentchev T, Ying G-S, et al. The role of apoptosis in age-related macular degeneration. Arch Ophtalmol. 2002;120(11):1435–1442.
  • De Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355(14):1474–1485.
  • Del Priore LV, Kuo Y-H, Tezel TH. Age-related changes in human RPE cell density and apoptosis proportion in situ. Invest Ophthalmol Vis Sci. 2002;43(10):3312–3318.
  • Ballinger SW, VAN Houten B, Conklin CA, et al. Hydrogen peroxide causes significant mitochondrial DNA damage in human RPE cells. Exp Eye Res. 1999;68(6):765–772.
  • Jin G-F, Hurst JS, Godley BF. Hydrogen peroxide stimulates apoptosis in cultured human retinal pigment epithelial cells. Curr Eye Res. 2001;22(3):165–173.
  • Godley BF, Jin G-F, Guo Y-S, et al. Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H2O2. Exp Eye Res. 2002;74(6):663–669.
  • Kalariya NM, Ramana KV, Srivastava SK, et al. Carotenoid derived aldehydes-induced oxidative stress causes apoptotic cell death in human retinal pigment epithelial cells. Exp Eye Res. 2008 Jan;86(1):70–80.
  • Cai J, Wu M, Nelson KC, et al. Oxidant-induced apoptosis in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40(5):959–966.
  • Sparrow JR, Nakanishi K, Parish CA. The lipofuscin fluorophore A2E mediates blue light–induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 2000;41(7):1981–1989.
  • Sparrow JR, Cai B. Blue light–induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci. 2001;42(6):1356–1362.
  • Fujihara M, Nagai N, Sussan TE, et al. Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice. PloS One. 2008;3(9):e3119.
  • Roduit R, Schorderet DF. MAP kinase pathways in UV-induced apoptosis of retinal pigment epithelium ARPE19 cells. Apoptosis. 2008;13(3):343–353.
  • Du H, Sun X, Guma M, et al. JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Nat Acad Sci. 2013;110(6):2377–2382.
  • Jiang S, Moriarty-Craige SE, Orr M, et al. Oxidant-induced apoptosis in human retinal pigment epithelial cells: dependence on extracellular redox state. Invest Ophthalmol Vis Sci. 2005;46(3):1054–1061.
  • Coto-Montes A, Boga JA, Rosales-Corral S, et al. Role of melatonin in the regulation of autophagy and mitophagy: a review. Mol Cell Endocrinol. 2012 Sep 25;361(1):12–23.
  • Sagrillo-Fagundes L, Bienvenue-Pariseault J, Vaillancourt C. Melatonin:the smart molecule that differentially modulates autophagy in tumor and normal placental cells. PloS One. 2019;14(1):e0202458.
  • Choi SI, Kim KS, Oh JY, et al. Melatonin induces autophagy via an mTOR‐dependent pathway and enhances clearance of mutant‐TGFBIp. J Pineal Res. 2013;54(4):361–372.
  • Chen J, Wang L, Wu C, et al. Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J Pineal Res. 2014 Jan 01;56(1):12–19.
  • Ding K, Xu J, Wang H, et al. Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. Neurochem Int. 2015 Dec 01;91:46–54.
  • Cao S, Shrestha S, Li J, et al. Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation. Sci Rep. 2017;7(1):2417.
  • Jeong J-K, Moon M-H, Lee Y-J, et al. Melatonin-induced autophagy protects against human prion protein-mediated neurotoxicity. J Pineal Res. 2012 Sep 01;53(2):138–146.
  • Liu C, Jia Z, Zhang X, et al. Involvement of melatonin in autophagy-mediated mouse hepatoma H22 cell survival. Int Immunopharmacol. 2012 Feb 01;12(2):394–401.
  • Jeong JK, Moon MH, Lee YJ, et al. Melatonin‐induced autophagy protects against human prion protein‐mediated neurotoxicity. J Pineal Res. 2012;53(2):138–146.
  • Shi L, Liang F, Zheng J, et al. Melatonin regulates apoptosis and autophagy via ROS-MST1 pathway in subarachnoid hemorrhage. Front Mol Neurosci. 2018;11:93.
  • Maejima Y, Kyoi S, Zhai P, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2 [Article]. Nat Med. 2013 Oct 20;19:1478.
  • Sanphui P, Biswas SC. FoxO3a is activated and executes neuron death via Bim in response to β-amyloid [Original Article]. Cell Death Dis. 2013 May 09;4:e625.
  • Cheung WL, Ajiro K, Samejima K, et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell. 2003;113(4):507–517.
  • Rosen RB, Hu D-N, Chen M, et al. Effects of melatonin and its receptor antagonist on retinal pigment epithelial cells against hydrogen peroxide damage. Mol Vis. 2012;18:1640–1648.
  • Chang -C-C, Huang T-Y, Chen H-Y, et al. Protective effect of melatonin against oxidative stress-induced apoptosis and enhanced autophagy in human retinal pigment epithelium cells. Oxid Med Cell Longev. 2018;2018:9015765.
  • Andrabi SA, Sayeed I, Siemen D, et al. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. Faseb J. 2004;18(7):869–871.
  • Suwanjang W, Abramov AY, Charngkaew K, et al. Melatonin prevents cytosolic calcium overload, mitochondrial damage and cell death due to toxically high doses of dexamethasone-induced oxidative stress in human neuroblastoma SH-SY5Y cells. Neurochem Int. 2016 Jul 01;97:34–41.
  • Koh P-O. Melatonin regulates the calcium-buffering proteins, parvalbumin and hippocalcin, in ischemic brain injury. J Pineal Res. 2012 Nov 01;53(4):358–365.
  • Martín M, Macías M, Escames G, et al. Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress. Faseb J. 2000;14(12):1677–1679.
  • López A, García JA, Escames G, et al. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res. 2009;46(2):188–198.
  • Acuna-Castroviejo D, Escames G, Rodriguez MI, et al. Melatonin role in the mitochondrial function. Front Biosci. 2007;12:947–963.
  • Radogna F, Cristofanon S, Paternoster L, et al. Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl‐2. J Pineal Res. 2008;44(3):316–325.
  • Radogna F, Paternoster L, Albertini MC, et al. Melatonin antagonizes apoptosis via receptor interaction in U937 monocytic cells. J Pineal Res. 2007;43(2):154–162.
  • Das A, McDowell M, Pava MJ, et al. The inhibition of apoptosis by melatonin in VSC4. 1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF‐α toxicity involves membrane melatonin receptors. J Pineal Res. 2010;48(2):157–169.
  • Fang J, Yan Y, Teng X, et al. Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress. Aging (Albany NY). 2018;10(10):2954–2972.
  • Osborne NN, Nash MS, Wood J. Melatonin counteracts ischemia-induced apoptosis in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1998;39(12):2374–2383.
  • Argun M, Tök L, Uğuz A, et al. Melatonin and amfenac modulate calcium entry, apoptosis, and oxidative stress in ARPE-19 cell culture exposed to blue light irradiation (405 nm). Eye. 2014;28(6):752.
  • Bardak H, Uğuz AC, Bardak Y. Protective effects of melatonin and memantine in human retinal pigment epithelium (ARPE-19) cells against 2-ethylpyridine-induced oxidative stress: implications for age-related macular degeneration. Cutan Ocul Toxicol. 2018;37(2):112–120.
  • Liang F-Q, Aleman TS, Yang Z, et al. Melatonin delays photoreceptor degeneration in the rds/rds mouse. Neuroreport. 2001;12(5):1011–1014.
  • Acuna Castroviejo D, C Lopez L, Escames G, et al. Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem. 2011;11(2):221–240.
  • Blasiak J, Reiter RJ, Kaarniranta K. Melatonin in retinal physiology and pathology: the case of age-related macular degeneration. Oxid Med Cell Longev. 2016;2016:6819736.
  • Kerenyi N, Balogh I, Somogyi E, et al. Cytochemical investigation of acetyl-serotonin-transferase activity in the pineal gland. Cell Mol Biol. 1979;25(4):259–262.
  • Tan D-X, Manchester LC, Qin L, et al. Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci. 2016;17(12):2124.

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