NO-mediated modulation of mitochondrial energy production by melatonin

Abstract

Melatonin is a hormone produced by the pineal gland following circadian rhythms, although many other cell types are able to produce it. This molecule is involved in many cell functions including regulation of specific enzymes involved in cell redox homeostasis, with impact on cell bioenergetics. Nitric oxide (NO) produced by the NOS (s) enzymes, influences cell bioenergetics modulating mitochondrial respiration at the level of Complex I and Complex IV, i.e. Cytochrome c oxidase (CcOx). The interaction of CcOx and NO, results in the fast and reversible inhibition of the enzyme, that may proceed through two alternative reaction pathways leading to different degree of inhibition of cell respiration. The prevalence of one pathway over the other might be linked to different patho-physiological condition, possibly influenced by the presence of signalling compounds. Our work was aimed at studying the effects of melatonin on NO-mediated regulation of cell energetics. HaCaT cells treated with melatonin showed a time and concentration-dependent increase of the nNOS mRNA production with higher accumulation of nitrites/nitrates compared to controls. At mitochondrial level, the bioenergetic parameters such as lactate accumulation, ATP production and mitochondrial membrane potential followed synchronous changes compatible with No inhibition of Complex IV. The results are discussed in the light of a metabolic shift (from OXPHOS to glycolisis) induced by melatonin and by the NO mediated modulation of the phosphorilation chain activity initiated by the melatonin.