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Review
, 23 (2)

Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions

Affiliations
Review

Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions

Russel J Reiter et al. Molecules.

Abstract

Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the "free radical theory of aging", including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age.

Keywords: electron transport chain; free radical theory of aging; free radicals; melatonin synthesis; melatonin uptake; oxidative phosphorylation; oxidative stress.

Conflict of interest statement

None of the authors have a conflict of interest.

Figures

Figure 1
Figure 1
The chemical reduction or the addition of energy to ground state oxygen generates products referred to as reactive oxygen species (ROS). The most reactive of these derivatives are peroxynitrite and the hydroxyl radical. The conversion of hydrogen peroxide to the hydroxyl radical requires a transition metal with the conversion usually being referred to as the Fenton reaction. The red asterisk (*) identifies products that have been reported to be directly scavenged by melatonin and its metabolites. The evidence of these scavenging reactions is much stronger for some ROS than for others. Melatonin also stimulates antioxidant enzymes, e.g., superoxide dismutases (SOD), glutathione peroxidases (GPx), and glutathione reductase (GRd) to indirectly remove toxic ROS. The most toxic species, i.e., peroxynitrite and the hydroxyl radical, are not enzymatically degraded; they can only be removed by a direct scavenger. CAT = catalase.
Figure 2
Figure 2
This figure illustrates the structure of a mitochondrion and the location of the complexes (CI-CV) that constitute the electron transport chain that engages in oxidative phosphorylation, which results in the generation of energy in the form of ATP. Free radicals are formed when electrons leak and reduce nearby oxygen (O2) molecules to form the superoxide anion radical (O2). CI releases electrons into the mitochondrial matrix, while CIII releases them into both the matrix and the intramembrane space. Once formed, the O2 can be dismutated by superoxide dismutase (SOD) to hydrogen peroxide (H2O2) with its eventual conversion to the hydroxyl radical (•OH). O2 can also couple with nitric oxide (NO•) to produce the peroxynitrite anion (ONOO). Since melatonin is both taken up and synthesized in mitochondria, it is in an optimal position to scavenge these toxic species.
Figure 3
Figure 3
The structure of melatonin and some of its metabolites that have been shown to detoxify reactive oxygen and reactive nitrogen species. Additionally, some of these have other actions that enhance their ability to reduce oxidative stress, e.g., chelation of transition metal ions, promotion of antioxidant enzymes, inhibition of pro-oxidant enzymes, reducing electron leaking from the respiratory chain complexes, etc. Also shown is the sequence by which these metabolites are formed. This sequential formation of metabolites from melatonin, along with their ability to scavenge radicals, is referred to as melatonin′s antioxidant cascade.
Figure 4
Figure 4
The oligopeptide transporters, PEPT1/2, have recently been reported to be present in mitochondrial membranes. These transporters are believed to move melatonin into mitochondria against a gradient. This may explain the much higher concentration of melatonin in mitochondria than in other subcellular compartments. Moreover, high melatonin levels in mitochondria would be consistent with the marked ability of this antioxidant to protect these organelles from free radical damage as it occurs during aging and as a result of diseases of aging that have a free radical component.
Figure 5
Figure 5
This is an illustration of what is referred to as the endosymbiotic theory for the origin of mitochondria (and chloroplasts) and why these organelles in present-day eukaryotes likely have the ability to produce melatonin. A couple of billion years ago, prokaryotes phagocytized proteobacteria, which are known to synthesize melatonin; these bacteria were initially digested and used as nutrition. During evolution, the ingested bacteria eventually developed a mutually-beneficial symbiotic relationship with the cells that ingested them and they evolved into mitochondria. When they did so, the evolved mitochondria retained the ability to produce melatonin (brown image). As a result, present-day eukaryotic cells synthesize melatonin as shown in several reports cited in the current review. Likewise, some of the same prokaryotes also engulfed photosynthetic, melatonin-producing bacteria which evolved into chloroplasts of plant cells (green image); chloroplasts also have been shown to be involved in melatonin synthesis. Since plant cells have both chloroplasts and mitochondria may explain why plants generally have higher cellular concentrations of melatonin than do animal cells, which only have mitochondria.
Figure 6
Figure 6
This figure is a flow diagram that links free radicals and the associated oxidative damage with the progression of the aging phenotype and the onset and development of age-related diseases. The cloud at the top lists many of the iterations of the free radical theory of aging that have been introduced over the last 60 years. In the current review, we discuss the evidence that melatonin could be relevant to the processes summarized. ROS = Reactive oxygen species; AD = Alzheimer disease; PD = Parkinson disease; HD = Huntington disease; MS = Multiple sclerosis; ALS = amyotrophic lateral sclerosis.

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