Melatonin transport into mitochondria

Abstract

Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole's protective actions. Melatonin's mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.

Melatonin — More than Just a Pineal Hormone

“…It seems that melatonin penetration through membranes is a process controlled by transporters. Recently, this view has been supported by findings on the involvement of oligopeptide transporters PEPT 1/2 and the organic anion transporter OAT3, which may play a role in the crossing of the plasma membrane as well as intracellular, especially mitochondrial membranes [29,30]. With regard to mitochondria, these findings may be of particular importance, because of the observed accumulation of melatonin in these organelles [31,32] and intramitochondrial signaling by the melatonin receptor MT 1 [33].…”

Extended Signaling by Melatonin

“…In fact, such an uptake was demonstrated in other investigations [51,52]. More recently, accumulation of melatonin became more probable by the involvement of transporters in melatonin uptake, in particular, the oligopeptide transporters PEPT1/2 [53]. However, this was not yet the end of the story.…”

Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma

“…MEL has been reported to act both as a direct free radical scavenger [70], and as an indirect antioxidant through the stimulation of antioxidant enzymes such as Superoxide dismutase [71]. MEL also promotes the synthesis of glutathione, an essential intracellular antioxidant [72], and it is able to increase the efficiency of the mitochondrial electron transport chain (ETC) thereby lowering electron leakage and reducing free radical generation [73,74]. This study provides additional evidence to suggest that MEL is protective against glutamateinduced neurotoxicity and these findings are in agreement with those obtained by other groups [68,75].…”