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Cited by 402Circadian rhythm and melatoninMitochondrial Function and Pathologymelanin and skin pigmentation

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Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

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Tan, Dun-Xian, Manchester, Lucien, Qin, Lilan, Reiter, Russel·2016·International Journal of Molecular Sciences
DOI 10.3390/ijms17122124PMC PMC5187924
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Abstract

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.

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Crossref · 10.3390/ijms17122124

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Figures

Figure 1 Large amounts of mitochondria are present in pinealocytes of the Syrian hamster (34,000×). Inset shows a longitudinal section of mitochondrion with cristae arranged like a string of beads (44,500×). Modified from Bucana et al. [89].
Figure 1 Large amounts of mitochondria are present in pinealocytes of the Syrian hamster (34,000×). Inset shows a longitudinal section of mitochondrion with cristae arranged like a string of beads (44,500×). Modified from Bucana et al. [89].CC BY · PubMed Central
Figure 2 Upper panel: The localization of the SNAT. Blue arrows: The mitochondria isolated from the oocytes of mice. White arrow: enlarged image from left side of the arrow tail. Red arrow: SNAT staining (black dot). SNAT: serotonin N-acetyltransferase; Low panel: Melatonin concentrations in mitochondrial culture media with 10−4 M serotonin (mean ± SEM) modified from He et al. [112].
Figure 2 Upper panel: The localization of the SNAT. Blue arrows: The mitochondria isolated from the oocytes of mice. White arrow: enlarged image from left side of the arrow tail. Red arrow: SNAT staining (black dot). SNAT: serotonin N-acetyltransferase; Low panel: Melatonin concentrations in mitochondrial culture media with 10−4 M serotonin (mean ± SEM) modified from He et al. [112].CC BY · PubMed Central
Figure 3 The similarities of mitochondrial dynamics in pinealocytes, brain neurons and cultured SH-SY5Y cells. Upper panel: Mitochondrial dynamics in pinealocytes (27,000×). (A) Condensed state; (B) Second intermediate state; (C) Third intermediate state; Middle panel: Mitochondrial dynamics in brain neurons of mice. (E) Mitochondrial fission induced by cadmium treatment; (F) The transition of mitochondrial fission and fusion in the animal treated with cadmium plus melatonin; (G) Mitochondrial fusion in control healthy animal; Lower panel: Mitochondrial dynamics in cultured SH-SY5Y cells (60,000×). (H) Mitochondrial fission induced by methamphetamine; (I) The transition of mitochondrial fission and fusion in cells treated with methamphetamine plus melatonin; (J) Mitochondrial fusion in control cells. The similarities of A, E and H; B, F and I; C, G and J are obvious. Mordified from [90,184,185].
Figure 3 The similarities of mitochondrial dynamics in pinealocytes, brain neurons and cultured SH-SY5Y cells. Upper panel: Mitochondrial dynamics in pinealocytes (27,000×). (A) Condensed state; (B) Second intermediate state; (C) Third intermediate state; Middle panel: Mitochondrial dynamics in brain neurons of mice. (E) Mitochondrial fission induced by cadmium treatment; (F) The transition of mitochondrial fission and fusion in the animal treated with cadmium plus melatonin; (G) Mitochondrial fusion in control healthy animal; Lower panel: Mitochondrial dynamics in cultured SH-SY5Y cells (60,000×). (H) Mitochondrial fission induced by methamphetamine; (I) The transition of mitochondrial fission and fusion in cells treated with methamphetamine plus melatonin; (J) Mitochondrial fusion in control cells. The similarities of A, E and H; B, F and I; C, G and J are obvious. Mordified from [90,184,185].CC BY · PubMed Central
Figure 4 A summary of the potential effects of melatonin on a mitochondrion. MPTP: mitochondrial permeability transition pore; UCP: uncoupling protein; ROS: reactive oxygen species; ETC: electron transport chain; Cyto C: cytochrome C; AFMK: a melatonin metabolite, N1-acetyl-N2-fomyl-5-methoxykynuramine, which is also a potent antioxidant. Melatonin is metabolized to AFMK by cytochrome C via pseudo-enzymatic process [77]. Upper panel: The targeting sites of melatonin on mitochondrion; green lines: inhibition; red arrows: activation; red dash arrows: the directions of the multiple steps of reactions; black arrows: directions; Lower panel: Summary of the outcomes induced by melatonin’s action on mitochondrion; upward arrowhead: activation; downward arrowhead: inhibition; horizontal arrowhead: preservation; connecting lines indicate hierarches of the events.
Figure 4 A summary of the potential effects of melatonin on a mitochondrion. MPTP: mitochondrial permeability transition pore; UCP: uncoupling protein; ROS: reactive oxygen species; ETC: electron transport chain; Cyto C: cytochrome C; AFMK: a melatonin metabolite, N1-acetyl-N2-fomyl-5-methoxykynuramine, which is also a potent antioxidant. Melatonin is metabolized to AFMK by cytochrome C via pseudo-enzymatic process [77]. Upper panel: The targeting sites of melatonin on mitochondrion; green lines: inhibition; red arrows: activation; red dash arrows: the directions of the multiple steps of reactions; black arrows: directions; Lower panel: Summary of the outcomes induced by melatonin’s action on mitochondrion; upward arrowhead: activation; downward arrowhead: inhibition; horizontal arrowhead: preservation; connecting lines indicate hierarches of the events.CC BY · PubMed Central

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Metadata

Authors
Tan, D.-X., Manchester, L., Qin, L., & Reiter, R.
Affiliations
The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Tan, Dun-Xian
  • Reiter, Russel
ORCID
Reiter, Russel
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2016-12-16
Volume
17
Issue
12
Pages
2124
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms17122124
PMC
PMC5187924
OpenAlex
W2563008150
Cited by
402
References
206
Citations by year
2026: 23 · 2025: 38 · 2024: 51 · 2023: 51 · 2022: 46 · 2021: 50 · 2020: 43 · 2019: 33 · 2018: 33 · 2017: 32
FWCI
3.48
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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, mitochondrial targeting, mitochondrial protection, mitochondrial dynamics, mitochondrial fission and fusion, mitochondrial biogenesis, mitochondrial permeability transition pore, uncoupling proteins, reactive oxygen species scavenging, mitochondrial membrane potential, mitophagy, acetyltransferase, oocytes, pinealocytes, circadian rhythm
MeSH terms
Mitochondrial Uncoupling Proteins, Mitochondrial Permeability Transition Pore, Animals, Antioxidants, Circadian Rhythm, Enzyme Activation, Humans, Melatonin, Mitochondria, Plants, Reactive Oxygen Species, Mitochondrial Membrane Transport Proteins, Membrane Potential, Mitochondrial, Mitochondrial Dynamics, Mitophagy

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