Previous studies performed by our research group and funded by various projects, have allowed us to demonstrate that mitochondria are a physiological and therapeutic target of melatonin and its metabolites. We have demonstrated that melatonin can stimulate the respiratory chain to regulate mitochondrial function and ATP production. Moreover, melatonin effectively counteracts mitochondrial dysfunction in various experimental models of sepsis, aging, and Parkinson disease. Through numerous research projects, we have demonstrated that melatonin can effectively counteract the nigrostriatal damage induced by different neurotoxins, including MPTP, in mice as well as in cultures of PC12 cells differentiated with NGF into dopaminergic neurons. Specifically, we observed that melatonin regulates dopamine levels in the striatum, prevents dopamine autoxidation, normalises complex I activity, ATP production, and redox status in mitochondria in the substantia nigra and striate nucleus of these mice. Likewise, melatonin synergises with selegiline (L-deprenyl) while these mice recover their motility, and aids the recovery of dopamine levels and tyrosine hydroxylase activity.
We also found that one of melatonin’s metabolites, N1-acetyl-5-methoxykynuramine (AMK), which is found in the brain, is more potent than melatonin itself in inhibiting neuronal nitric oxide synthase (nNOS) in the brain. In addition, we observed that mitochondria actively capture melatonin and its metabolites in a concentration and time-dependent manner, and that these exert a protective effect within this organelle to maintain its homeostasis. We showed that melatonin protects the mitochondria present in tongue tissues in irradiated rats, thus preventing mucositis. In a more recent project, we are using zebrafish as an experimental model of neurodegeneration, to evaluate the effect of neuroprotective compounds (extracted from microbes) on mitochondria and their potential as therapeutic targets. We have also shown that, because melatonin is a mitochondrial protector, it can regenerate skin by delaying and/or reversing the symptoms of aging.
These properties of melatonin (and its metabolites) may be of great importance in regulating processes which depend on the modulation of mitochondrial bioenergetics. Recent studies have shown that the differentiation of neural stem cells is accompanied by changes in mitochondrial mass, both ATP and reactive oxygen species production, and the expression of antioxidant enzymes. Therefore, molecules that can induce changes in mitochondrial function could play a very important role in the regeneration of different tissues, including the skin.