Melatonin combats molecular terrorism at the mitochondrial level

Abstract

The intracellular environmental is a hostile one. Free radicals and related oxygen and nitrogen-based oxidizing agents persistently pulverize and damage molecules in the vicinity of where they are formed. The mitochondria especially are subjected to frequent and abundant oxidative abuse. The carnage that is left in the wake of these oxygen and nitrogen-related reactants is referred to as oxidative damage or oxidative stress. When mitochondrial electron transport complex inhibitors are used, e.g., rotenone, 1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine, 3-nitropropionic acid or cyanide, pandemonium breaks loose within mitochondria as electron leakage leads to the generation of massive amounts of free radicals and related toxicants. The resulting oxidative stress initiates a series of events that leads to cellular apoptosis. To alleviate mitochondrial destruction and the associated cellular implosion, the cell has at its disposal a variety of free radical scavengers and antioxidants. Among these are melatonin and its metabolites. While melatonin stimulates several antioxidative enzymes it, as well as its metabolites (cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxykynuramine), likewise effectively neutralize free radicals. The resulting cascade of reactions greatly magnifies melatonin's efficacy in reducing oxidative stress and apoptosis even in the presence of mitochondrial electron transport inhibitors. The actions of melatonin at the mitochondrial level are a consequence of melatonin and/or any of its metabolites. Thus, the molecular terrorism meted out by reactive oxygen and nitrogen species is held in check by melatonin and its derivatives.

Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials

“…We recently reviewed the mechanisms by which melatonin improves mitochondrial respiration and increases ATP synthesis under physiological and poisonous conditions (80). Consequently, the antioxidant and free-radical-scavenging capacities of melatonin protect proteins of the ETC and mtDNA from ROS/RNSinduced oxidative damage.…”

Pinealectomy aggravates acute pancreatitis in the rat

“…Under normal conditions, these free radicals are generated by mitochondrial metabolism and immediately neutralized by enzymatic and non-enzymatic natural scavengers [38]. During inflammation, the normal antioxidative system is inadequate due to the accelerated production of free radicals [25].…”

“…During inflammation, the normal antioxidative system is inadequate due to the accelerated production of free radicals [25]. Melatonin acts as a non-enzymatic scavenger [33,37,47] and as an activator of antioxidative enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) [3,16,25,38,41]. In addition, melatonin stabilizes lipid membranes, protects the membranes from peroxidation and modulates the immune response of the organism [9,27,31,45].…”

Melatonin as a stabilizer of mitochondrial function: role in diseases and aging

“…As it has been mentioned, mitochondria are major sites of free radical production and it is largely recognized that melatonin acts as a scavenger of free radicals already formed. Thereby, high concentrations of melatonin within mitochondria would be advantageous to avoid oxidative damage, due to the antioxidant properties of the molecule (Reiter et al, 2008). In this way, related to inner mitochondrial membrane essential components, not only are the above mentioned protein complexes of ETC protected from the harmful effects caused by reactive oxygen/nitrogen species (ROS/RNS), but also phospholipidic elements are safeguarded from lipid peroxidation (Stetinová et al, 2002).…”