Intrinsically synthesized melatonin in mitochondria and factors controlling its production.

The percentage of the total amount of melatonin produced in vertebrates that comes from the pineal is small (likely <5%) but, nevertheless, functionally highly noteworthy. The significance of pineal melatonin is that it is secreted cyclically such that it has a critical function in influencing not only the suprachiasmatic nucleus but clock genes that reside in perhaps every cell throughout the organism. Extrapineal melatonin, which may be synthesized in the mitochondria of all other cells in much larger amounts than that in the pineal gland has a different function than that derived from the pineal gland. Its synthesis is not circadian and it is not directly impacted by the photoperiodic environment. Also, melatonin from the extrapineal sites is not normally secreted into the blood stream; rather, it acts locally in its cell of synthesis or, possibly via paracrine mechanisms, on immediately adjacent cells. The functions of extrapineal melatonin include central roles in maintaining molecular and redox homeostasis and actions in resisting pathological processes due to its ability to directly or indirectly detoxify free radicals. The vast majority of organisms that exist on Earth lack a pineal gland so pineal-derived melatonin is unique to vertebrates. Evidence suggests that all invertebrates, protists and plants synthesized melatonin and they have no pineal homolog; thus, the production of melatonin by extrapineal cells in vertebrates should not be unexpected. While the factors that control pineal melatonin synthesis are well documented, the processes that regulate extrapineal melatonin production are undefined.