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Review
. 2017 Nov;74(21):3863-3881.
doi: 10.1007/s00018-017-2609-7. Epub 2017 Sep 1.

Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas

Russel J Reiter  1 , Sergio Rosales-Corral  2 , Dun Xian Tan  3 , Mei Jie Jou  4   5 , Annia Galano  6 , Bing Xu  3
Affiliations
Review

Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas

Russel J Reiter et al. Cell Mol Life Sci. 2017 Nov.

Abstract

Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin's chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin's high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.

Keywords: Apoptosis; Cytochrome c; Free radical-related diseases; Inner mitochondrial membrane; Melatonin transporters; Mitochondrial transition pore; Reactive oxygen species; SIRT3.

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Figures

Fig. 1
Fig. 1
A small percentage of oxygen inhaled/utilized by aerobic organisms generates oxygen-based derivatives, often called reactive oxygen species (ROS), that can damage critical molecules within cells. Some of the derivatives are free radicals [with an unpaired electron represented by the dot (·)] and others are not, e.g., hydrogen peroxide. The superoxide anion radical is quickly metabolized by superoxide dismutase (SOD) to hydrogen peroxide which can be removed from the intracellular environment by either catalase (CAT) or glutathione peroxidase (GPx). Oxidized glutathione (GSSG) is converted back to reduced glutathione (GSH) by glutathione reductase (GRd). The most destructive derivatives of oxygen are the hydroxyl radical and peroxynitrite. The hydroxyl radical is formed from hydrogen peroxide during the Fenton reaction and peroxynitrite is generated when the superoxide anion couples with nitric oxide. A large percentage of the ROS formed within cells is produced in mitochondria as a consequence of the leakage of electrons (e−) from the electron transport chain
Fig. 2
Fig. 2
The mitochondrial respiratory chain utilizes oxygen to generate energy in the form of ATP. Free radicals and reactive oxygen species are formed when electrons that are passed between successive complexes are fumbled and chemically reduce adjacent oxygen molecules. The toxic derivatives of oxygen, since the majority are formed in mitochondria, especially damage mitochondrial DNA, proteins and lipids. Because mitochondria are a primary source of toxic derivatives of oxygen, an antioxidant positioned in mitochondria would be especially important in reducing oxidative damage
Fig. 3
Fig. 3
Melatonin is believed to exist in most, possibly all, animal and plant species. It predictably evolved 3.0–2.5 billion years ago in photosynthetic cyanobacteria as an antioxidant; this function has been retained to the present day including in humans. Other functions of melatonin, many more than are shown in this figure, appeared at later stages of evolution. Reprinted with permission from Manchester et al. [13]
Fig. 4
Fig. 4
Fluorescence imaging of reactive oxygen species generation in cultured astrocytes, especially in the mitochondria, and the inhibition of ROS by melatonin. a An enhanced pseudocolor image which documents the higher ROS levels in mitochondria (yellow to red) than in other subcellular compartments. b–d Rapid increase in mitochondrial ROS formation in astrocytes exposed to an oxidant, H2O2, as visualized using dihydrorhodamine 123; a before exposure to H2O2; b at 5 min and c at 10 min following the addition of H2O2. In addition to being much brighter, the mitochondria in the H2O2-exposed cells are swollen. e, f When melatonin was added to the culture medium simultaneously with H2O2, ROS levels in the mitochondria did not increase at either 5 or 10 min, consistent with the ability of melatonin to enter the mitochondria and neutralize the ROS. Reprinted with permission Jou et al. [95]
Fig. 5
Fig. 5
Fluorescence detected by flow cytometry (FACS) analysis of ROS generation in astrocytes after exposure to one of several oxidants: H2O2, tert-butyl hydroperoxide (t-BuOOH) or cumene hydroperoxide (Cu-OOH). a Illustrates the dose-dependent increase in mitochondrial ROS induced by H2O2 (0.1, 1.0 or 10 mM). b The addition of melatonin (100 µM) with H2O2 greatly diminished ROS fluorescence. c When 100 µM vitamin E was exchanged for melatonin, it was much less effective than melatonin in reducing mitochondrial ROS. d, e Melatonin also significantly lowered ROS generation in cells exposed to either t-BuOOH or Cu-OOH, respectively. f Melatonin inhibition of ROS-mediated by H2O2 exposure. Reprinted with permission from Jou et al. [95]
Fig. 6
Fig. 6
The induction of cellular apoptosis after exposure to an oxidant involves the release of cytochrome c from damaged mitochondria with the subsequent activation of caspases leading to programmed cell death. This figure illustrates the localizations of cytochrome c in the mitochondria of astrocytes not exposed to an oxidant (top); middle after 90 min exposure to H2O2; bottom after exposure to H2O2 plus melatonin. Clearly, H2O2 treatment caused a massive release of cytochrome c into the cytosol and much less into the nucleus with melatonin almost totally preventing this escape. The release of cytochrome c occurred simultaneously with retraction of cell processes, shrinkage of the cells and an irregular plasma membrane. Cytochrome c was detected using immunocytochemistry and laser scanning confocal microscopy. Bar 10 µM. Reprinted with permission from Jou et al. [95]
Fig. 7
Fig. 7
The endosymbiotic theory of the origin of mitochondria and chloroplasts. Mitochondria arose from engulfed bacteria that were initially taken in and digested for their nutrients. During evolution, the ingested bacteria developed a symbiotic relationship with the host cell and evolved into mitochondria. Likewise, photosynthetic bacteria were also taken in as food but eventually evolved to form chloroplasts. Since, the ingested bacteria (which formed both mitochondria and chloroplasts) produced melatonin, we proposed this function was retained such that in current day animals and plants, both mitochondria and chloroplasts retain the ability to produce melatonin. Emerging evidence supports this assumption. Reprinted with permission from Manchester et al. [13]
Fig. 8
Fig. 8
The targeting of melatonin to the mitochondria; evidence suggests that melatonin enters the mitochondria through specific transporters, PETP 1/2 (oligopeptide transporters). The actions of melatonin in mitochondria are multiple. These actions, particularly including its ability to reduce oxidative damage to critical mitochondrial molecules, preserve the function of these organelles and benefit diseases in which mitochondrial malfunction is a feature. Melatonin increases the efficiency of the electron transport chain (I, II, III and IV) and improves ATP production (ATP synthase). Reactive oxygen species (ROS) produced when electrons leak from the ETC are directly scavenged by melatonin and its metabolite [N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK)]. ROS are also metabolized by mitochondria superoxide dismutase (SOD2) and scavenged by glutathione (GSH) and SIRT3. Melatonin also modulates uncoupling protein (UCP2) to maintain an optimal inner mitochondrial membrane potential and prevents opening of the mitochondrial permeability transition pore (MPTP). This limits the escape of cytochrome c when the mitochondrion is damaged by ROS. Recent evidence suggests that melatonin, in addition to quickly entering the mitochondria, may also be synthesized in this organelle (5HT → Mel) where it is also metabolized to AFMK. Not shown in this figure are other actions of melatonin that prevent mitochondrial damage and cell death. These include a reduction in oxidative damage to lipids, proteins and DNA, upregulation of antiapoptotic proteins and downregulation of proapoptotic proteins and a suppression of the activities of caspases which execute the apoptosis pathway
Fig. 9
Fig. 9
The structure of synthetically produced, mitochondria-targeted antioxidants, i.e., MitoE and MitoQ. When vitamin E or co-enzyme Q10 is coupled to the triphosphonium cation, they more readily accumulate in the cytosol and in the mitochondria due to their increased lipid solubility. With regard to mitochondria, these synthetically produced antioxidants accumulate in concentrations of 200-–500-fold greater than unconjugated vitamin E and co-enzyme Q10. Despite this high concentration, when compared under in vivo experimental conditions, melatonin at equimolar concentrations was as good as or better than the fabricated antioxidants in protecting against cellular oxidative stress. For this and other reasons, we consider melatonin to be a mitochondria-targeted antioxidant. IMM inner mitochondrial membrane, OMM outer mitochondrial membrane
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