The DOI matches its Crossref record; 158 of the 168 references it cites were found in a registry or an index.
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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In the citing paper
“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]
Citations
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Items 101–156 of 156
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“Indeed, there is now strong evidence that melatonin is produced in every animal cell that has mitochondria (55).”
BackgroundMelatonin as a Chronobiotic/Cytoprotective Agent in REM Sleep Behavior Disorder
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“Melatonin functions in abiotic adaptation through repairing ruptured mitochondria and chloroplast in plants (Lee and Back, 2019; Tan and Reiter, 2019).”
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“Introduction Melatonin, a tryptophan (Trp) metabolism product, is widely detected in many species, including animals, plants, unicellular eukaryotes, algae, bacteria and humans [1,2].”
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Melatonin Inhibits Peroxide Production in Plant Mitochondria
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“Mitochondrial cytochrome P450 1B1 (CP4501B1) metabolizes melatonin to N-acetylserotonin (NAS) into tumor cells, which can induce apoptosis [5].”
BackgroundZghari, O., Azirar, S., Lamtai, M., et al. (2023) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-023-01465-x · Cited by 9
“…anti-inflammatory, regulatory and immunomodulatory properties, which have already been shown in humans and rodents, this hormone and its metabolites have properties that can combat oxidative stress and stimulate the activation of molecules that help synaptic plasticity in the nervous system [4–6].”
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“All tissues containing mitochondria can produce melatonin [7,8].”
BackgroundTemporal expression patterns of the melatoninergic system in the human thymus of children
Cruz‐Chamorro, I., Álvarez‐Sánchez, N., Escalante-Andicoechea, C., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.07.007 · Cited by 7
“In fact, the recent evidence about melatonin is mainly synthesized in the mitochondria from several tissues lead us to think that the thymus would not be an exception [32], especially if we consider that in eukaryotes, mitochondria are the major source of reactive oxygen species (ROS) and they require specific onsite…”
BackgroundMelatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids
Loh, D., & Reiter, R. J. (2025) · Exploration of neuroscience · doi:10.37349/en.2025.100678 · Cited by 6
Self-citationAdvances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications
Reiter, R. J., Sharma, R., Rosales‐Corral, S., Coto‐Montes, A. M., Boga, J. A., & Vriend, J. P. (2020) · Human perspectives in health sciences and technology · doi:10.1007/978-3-030-32857-3_14 · Cited by 6
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Serotonin and Melatonin: Role in Rhizogenesis, Root Development and Signaling
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Lower plasma melatonin levels in non-hypoxic premature newborns associated with neonatal pain
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“Deficiency of melatonin at the mitochondrial level may be the primary cause of free radical diseases, rather than plasma melatonin levels, as melatonin synthesis and metabolization occur significantly at the mitochondria [18–20].”
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Melatonin Enhances Anti-tumoral Effects of Menadione on Colon Cancer Cells
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“Functional expression of MT2 (Mel1b) melatonin receptors in human PAZ6 adipocytes / L. Brydon, L. Petit, P. Delagrange et al. // Endocrinology, 2001.”
BackgroundMelatonin Reprograms Glucose Metabolism in Cancer Cell Mitochondria
Reiter, R. J. (2019) · Series of Endocrinology Diabetes and Metabolism · doi:10.54178/jsedmv1i3001 · Cited by 3
Self-citationPustelnik, K., Burner, T., Hoetzenecker, W., & Fischer, T. W. (2026) · Experimental Dermatology · doi:10.1111/exd.70235 · Cited by 3
“…has already been extensively shown to harbour potent antioxidative, radical scavenging and UVR damage-preventive properties [24–33 Melatonin's [59, 60] and its metabolites' [36, 44, 57, 60–63] antioxidative and DNA repair mechanisms require high local concentrations (1–1000 μM) and act…”
Wang, D., Yu, H., Li, Y., Xu, Z., Shi, S., Dou, D., Sun, L., Zheng, Z., Shi, X., Deng, X., et al. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10446 · Cited by 2
“Melatonin is a mitochondrial targeting antioxidant, which is synthesized in mitochondria, and the mitochondria are also the sites of melatonin metabolism (27).”
BackgroundEbru, U., Kılıçaslan, D., Kurt, A. H., Alli, B., & Doğaner, A. (2021) · Pharmaceutical Chemistry Journal · doi:10.1007/s11094-021-02490-1 · Cited by 2
Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer’s DiseasePreprint
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Reactive Nitrogen Species (RNS) and Melatonin Interaction in Plant
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Exploring melatonin’s therapeutic potential in neurological disorders: a review of current evidence
Singh, M., Maru, S., Sugunan, S., Pandit, A., Wadhwa, P. K., & Rajput, P. (2024) · Biological Rhythm Research · doi:10.1080/09291016.2024.2430563 · Cited by 1
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Melatonin Receptor 2 Promotes Lipid Metabolism of Cumulus-oocyte Complexes via the cAMP/PKA PathwayPreprint
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Melatonin and the Chronobiology of Drug Abuse
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The role of antioxidant supplementation in neuronal disorders
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Taşdemir, S., Bülbül, M. V., Kalay, B., et al. (2026) · International Journal of Translational Medicine · doi:10.3390/ijtm6040044
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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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