Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics - PubMed (original) (raw)

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Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Dun-Xian Tan et al. Int J Mol Sci. 2016.

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.

Keywords: antioxidant; melatonin; mitochondria; mitochondrial dynamics; mitophagy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

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 2

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 3

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 4

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, _N_1-acetyl-_N_2-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.

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