Advances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications

Melatonin, N-acetyl-5-methoxy-tryptamine, was discovered to be a product of serotonin metabolism in the mammalian pineal gland where its synthesis is under control of the light:dark cycle. Besides its regulatory pathway involving ganglion cells in the retina, the neural connections between the eyes and the pineal gland include the master circadian clock, the suprachiasmatic nuclei, and the central and peripheral nervous systems. Since pineal melatonin is released into the blood and into the cerebrospinal fluid, it has access to every cell in an organism and it mediates system-wide effects. Subsequently, melatonin was found in several extrapineal organs and, more recently, perhaps in every cell of every organ. In contrast to the pinealocytes, non-pineal cells do not discharge melatonin into the blood; rather it is used locally in an intracrine, autocrine, or paracrine manner. Melatonin levels in non-pineal cells do not exhibit a circadian rhythm and do not depend on circulating melatonin concentrations although when animals are treated with exogenous melatonin it is taken up by presumably all cells. Mitochondria are the presumed site of melatonin synthesis in all cells; the enzymatic machinery for melatonin synthesis has been identified in mitochondria. The association of melatonin with mitochondria, because of its ability to inhibit oxidative stress, is very fortuitous since these organelles are a major site of damaging reactive oxygen species generation. In this review, some of the actions of non-pineal-derived melatonin are discussed in terms of cellular and subcellular physiology.