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Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells
Open accessAbstract
It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated.
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“Recently obtained results indicate that mitochondria play an important role in the production, metabolism, and activity of melatonin (Tan et al. 2016; Tan and Reiter 2019).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Tan and Reiter 2019
In the citing paper
“Newer data indicate that the mitochondria are pivotal for several aspects of melatonin: its production, metabolism, and activity through receptors [35].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [35]
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Cited by
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“Because melatonin is highly lipophilic, it can pass through all morphophysiological barriers from the circulatory system; it likely gets into every cell and plays a critical role in all tissues [15].”
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“During OXPHOS, ROS are abundantly formed, and melatonin, as an indiscriminate radical scavenger (67) (FIGURE 1), is in an ideal position to incapacitate these damaging brigands.”
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“The plant chloroplast and mitochondria are significant sites of MT biosynthesis, and it does not preclude the possibility that some MT is not also formed in cell cytosol (Tan and Reiter, 2019).”
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“The SNAT-catalyzed reaction is the penultimate step; the SNAT gene family plays pivotal roles in terms of melatonin synthesis regulation in both plants and animals [41].”
BackgroundAnderson, G., Rodriguez, M., & Reiter, R. J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215500 · Cited by 86
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Self-citationMitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment
Mehrzadi, S., Hemati, K., Reiter, R. J., & Hosseinzadeh, A. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1737015 · Cited by 82
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He, H., & He, L. (2020) · Physiologia Plantarum · doi:10.1111/ppl.13143 · Cited by 80
Boosting immune system against cancer by melatonin: A mechanistic viewpoint
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“such as archaea, bacteria, algae, protozoa, fungi, plants, invertebrates, and vertebrates [3,4].”
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“However, findings on higher tissue levels of melatonin and of mitochondrial accumulation (222, 263) let this possibility appear in a new light.”
Evolutionary formation of melatonin and vitamin D in early life forms: insects take centre stage
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“Similar functions have been assigned to melatonin and its derivatives (Reiter & Tan, 2019; Zhao et al ., 2019; Reiter et al ., 2017; Tan et al ., 2007, 2013, 2014; Vijayalaxmi et al ., 2004; Slominski et al ., 2014 c , 2017 d ; Janjetovic et al ., 2017; Skobowiat et al ., 2018).”
Self-citationSlominski, A. T., Kim, T., Slominski, R. M., Song, Y., Qayyum, S., Placha, W., Janjetović, Z., Kleszczyński, K., Atigadda, V. R., Song, Y., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015496 · Cited by 67
“Melatonin also stimulates antioxidative responses and DNA repair pathways, which require high local concentrations (1–1000 µ M) of the compound and are MT1-and MT2-independent [20–22].”
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Self-citationBenefits and adverse events of melatonin use in the elderly (Review)
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Characterization of serotonin and N ‐acetylserotonin systems in the human epidermis and skin cells
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“Interestingly, mitochondria are the main sites for melatonin synthesis in various cells, including neurons [59, 60].”
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“37 The mitochondrial aspects of melatonin activity deserve to be considered.”
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Self-citationEffects of Light Quality and Phytochrome Form on Melatonin Biosynthesis in Rice
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“Indeed, the mitochondria are crucial for melatonin synthesis, metabolism, and activity [5].”
BackgroundFunctional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium
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Melatonin’s Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights
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“Additionally, melatonin is generated locally in most cells, tissues, and organs, including lymphocytes, bone marrow, the thymus, the gastrointestinal system, the skin, and the eyes, where it can have an autocrine or paracrine role(38) Indeed, there is now compelling evidence that melatonin is synthesized in every anim…”
BackgroundEmamverdian, A., Ghorbani, A., Pehlivan, N., Alwahibi, M. S., Elshikh, M. S., Liu, G., Li, Y., Barker, J., Zargar, M., & Chen, M. (2023) · Scientia Horticulturae · doi:10.1016/j.scienta.2023.112433 · Cited by 30
Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?
Cardinali, D. P. (2019) · Melatonin Research · doi:10.32794/mr11250025 · Cited by 29
Anderson, G. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.07.014 · Cited by 28
Increased Oxidative Stress Markers in Acute Ischemic Stroke Patients Treated with Thrombolytics
Pawluk, H., Kołodziejska, R., Grześk, G., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415625 · Cited by 27
Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub
Anderson, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010350 · Cited by 32
He, L., Cui, X., Xia, Q., Li, F., Mo, J., Gong, J., Zhang, Y., & Zhang, J. J. (2019) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2019.09.012 · Cited by 27
Chen, Y.-T., Huang, C., Chang, C., Chiang, J. Y., Luo, C., Chen, H., & Yip, H. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.48358 · Cited by 26
“Melatonin (Mel), synthesized in mitochondria and thus, most cells in human being can synthesize this small molecule [22], has been identified to be a robust antioxidant [23, 24] that strongly suppressed the formation of reactive oxygen species and attenuated inflammation.”
BackgroundResultAssociations of ozone exposure with urinary metabolites of arachidonic acid
He, L., Lin, Y., Wang, X., Liu, X., Wang, Y., Qin, J., Wang, X., Day, D. B., Xiang, J., Mo, J., et al. (2020) · Environment International · doi:10.1016/j.envint.2020.106154 · Cited by 27
The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy
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Dark secrets of phytomelatonin
Chen, Q., Hou, S., Pu, X., Li, X., Li, R., Yang, Q., Wang, X., Guan, M., & Rengel, Z. (2022) · Journal of Experimental Botany · doi:10.1093/jxb/erac168 · Cited by 26
Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status
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Paulino, L. R. F. M., Barroso, P. A. A., Silva, J. R. V., et al. (2022) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2022.106750 · Cited by 25
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Aktan, A. K., AKBULUT, K. G., Abdi, S., & Akbulut, H. (2021) · Biologia Futura · doi:10.1007/s42977-021-00102-3 · Cited by 24
“2018; Tan and Reiter 2019).”
Effect of melatonin on exosomal dynamics in bovine cumulus cells
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Phytomelatonin in stress management in agriculture
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Shi, F., Qiu, J., Zhang, S., Zhao, X. J., Feng, D., & Feng, X. (2021) · Environmental Pollution · doi:10.1016/j.envpol.2021.118445 · Cited by 21
He, L., Norris, C. L., Cui, X., Li, Z., Barkjohn, K. K., Teng, Y., Fang, L., Lin, L., Wang, Q., Zhou, X., et al. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145709 · Cited by 22
The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature
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Hwang, O. J., & Back, K. (2021) · Molecules · doi:10.3390/molecules26041075 · Cited by 20
Differential susceptibility of retinal ganglion cell subtypes against neurodegenerative diseases
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Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia
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Melatonin — This is important to know
Kołodziejczyk, I., & Kaźmierczak, A. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.170871 · Cited by 19
Metadata
- Authors
- Tan, D.-X., & Reiter, R. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- ORCID
- Reiter, Russel. J.
- Venue
- Melatonin Research
- Publisher
- ST Bio-life
- Published
- 2019-02-28
- Volume
- 2
- Issue
- 1
- Pages
- 44-66
- ISSN
- 2641-0281 (ISSN-L)
- OpenAlex
- W2919912171
- Cited by
- 172
- References
- 168
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 12 · 2023: 20 · 2022: 20 · 2021: 38 · 2020: 41 · 2019: 32
- FWCI
- 18.08
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Melatonin Research (publishedVersion, cc-by)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Keywords
- melatonin synthesis, mitochondria, serotonin N-acetyltransferase, mitochondrial matrix, intermembrane space, melatonin receptors, MT1 receptor, MT2 receptor, cerebral ischemia-reperfusion injury, neuronal injury, N-acetylserotonin, melatonin metabolism, circadian rhythm, anticancer activity
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