Abstract
It was a surprising discovery when mitochondria,
 as the power houses of cells, were also found to synthesize the potent
 mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin
 N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space
 of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix
 due to substrate (N-acetyl co-enzyme A) availability while the intermembrane
 space may serve as the recycling pool of SNAT to regulate the melatonin
 circadian rhythm. Another surprise was that the melatonin membrane receptors,
 including MT1 and MT2, were also present in mitochondria. The protective
 effects of melatonin against neuronal injury induced by brain ischemia/reperfusion
 were proven to be mainly mediated by mitochondrial melatonin receptors rather
 than the cell surface membrane receptors which is contrary to the classical
 principle. In addition, melatonin metabolic enzyme has also been identified in
 the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to
 strengthen the antitumor effects of melatonin. Thus, mitochondria are the
 generator, battle ground and metabolic sites of melatonin. The biological
 significance of the strong association between mitochondria and melatonin
 should be intensively investigated.
Highlights
The results indicated that during normal condition, a majority of melatonin was the product of acetylserotonin methyltrasferase (ASMT) as the last enzyme; under stressful conditions, the major part of melatonin was generated by catalytic activity of serotonin N-acetyltransferase (SNAT) as the final enzyme [49]
The discovery that melatonin is mainly synthesized in the mitochondria had been hypothesized [5] and it seems that this is a universal phenomenon which occurs in different species and different cell types
Considering that mitochondria are the main source of reactive oxygen species (ROS) and melatonin is a mitochondrial-targeted antioxidant, this discovery is consistent with what might be expected
Summary
It has been speculated that the melatonin synthetic gene, SNAT in eukaryotes, was transferred from bacteria. The DNA sequences and protein structures of SNAT from bacteria to vertebrates have evolved significantly, especially in the regulatory parts of this enzyme [4]; the structure of their product, melatonin, has not been modified. This is likely attributed to melatonin’s important function as an optimal antioxidant. It is calculated that a melatonin molecule may scavenge up to 10 ROS [26, 27] It stimulates the activity of the mitochondrial antioxidative enzymes, Mn-SOD in animals and in plants [28-31]. To better understand the importance of melatonin in mitochondria, in this review, we briefly discuss the recent developments regarding mitochondrial melatonin synthesis, metabolism and some activities of melatonin on mitochondrial functions as well as their dynamics
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