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

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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.

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Fig. 1
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Reprinted with permission from Manchester et al. [13]

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Reprinted with permission Jou et al. [95]

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Reprinted with permission from Jou et al. [95]

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Reprinted with permission from Jou et al. [95]

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Reprinted with permission from Manchester et al. [13]

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Acknowledgements

This work was supported in part by Grants CMRPD1C0511-3 (from the Chang Gung Memorial Hospital, Taiwan), MOST 105-2320-B-182-011 and MOST 104-2320-B-182-008 (to MJJ).

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Authors and Affiliations

  1. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA

    Russel J. Reiter, Dun Xian Tan & Bing Xu

  2. Centro de Investigacion Biomedica de Occidente, Del Instituto Mexicana del Seguro Social, 44340, Guadalajara, Mexico

    Sergio Rosales-Corral

  3. Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyüan, Taiwan

    Mei Jie Jou

  4. Department of Neurology, Kee-Lung Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan

    Mei Jie Jou

  5. Departemento de Quimica, Uninversidad Autonoma Metropolitana-Iztapalapa, 09340, Mexico City, Mexico

    Annia Galano

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  1. Russel J. Reiter
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Correspondence to Russel J. Reiter.

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Reiter, R.J., Rosales-Corral, S., Tan, D.X. et al. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell. Mol. Life Sci. 74, 3863–3881 (2017). https://doi.org/10.1007/s00018-017-2609-7

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