Melatonin, mitochondria, and cellular bioenergetics

Aerobic cells use oxygen for the production of 90-95% of the total amount o f ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxida tive phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidas e. under normal conditions a small percentage of oxygen may be reduced by o ne, two. or three electrons only, yielding superoxide anion, hydrogen perox ide, and the hydroxyl radical, respectively. The main radical produced by m itochondria is superoxide anion and the intramitochondrial antioxidant syst ems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production. During aging and some neurodegenerative diseases, oxidatively damaged mitochondria are unable to maintain the energy demands of the cell leading to an increased production of free radicals. Both proce sses, i.e., defective ATP production and increased oxygen radicals, may ind uce mitochondrial-dependent apoptotic cell death. Melatonin has been report ed to exert neuroprotective effects in several experimental and clinical si tuations involving neurotoxicity and/or excitotoxicity. Additionally, in a series of pathologies in which high production of free radicals is the prim ary cause of the disease, melatonin is also protective. A common feature in these diseases is the existence of mitochondrial damage due to oxidative s tress. The discoveries of new actions of melatonin in mitochondria support a novel mechanism, which explains some of the protective effects of the ind oleamine on cell survival.