Dr. Russel Reiter

Abstract:

Melatonin is synthesized in the mitochondrial matrix of every cell where it functions as a potent antioxidant [1].  Its position in the mitochondria is fortuitous since these organelles are major contributors to the production of free radicals [reactive oxygen species (ROS) and reactive nitrogen species (RNS)].  Free radicals indiscriminately damage lipids, proteins, DNA, etc.; the damaged molecules contribute to cellular deterioration, organ dysfunction and aging.  The destroyed molecules are referred to as oxidative stress [2].   Melatonin has documented efficacy in slowing the progression of numerous serious diseases that have a free radical component related to their pathophysiology by preventing oxidative stress.  Melatonin has this action in neurodegenerative diseases, cancer, osteoporosis, drug-induced organ failure, etc.  Many pathological cells, but most thoroughly studied in cancer cells, alter their means of processing glucose such that they switch from conventional oxidative phosphorylation (OXPHOS) to aerobic glycolysis for energy (ATP) production [3].  This gives the pathological cells an advantage which helps the disease to progress. This abnormal metabolic activity is referred to as Warburg-type metabolism and occurs when pyruvate, an end product of glucose metabolism, is prevented from entering the mitochondria due to the inhibition of the enzyme pyruvate dehydrogenase (PDH) which normally converts pyruvate into acetyl coenzyme A (acetyl CoA).  Acetyl CoA is important for supporting OXPHOS and also for mitochondrial melatonin synthesis; so, melatonin levels fall [4]. Thus, the massive number of free radicals in the mitochondria go uncontested and cause extensive metabolic disturbances contributing to disease progression.  In cancer cells, Warburg-type metabolism also leads to chemoresistance.  Treatment of pathological cells with melatonin elevates its levels in the mitochondrial matrix, reverses Warburg metabolism back to normal OXPHOS, and also overcomes cancer chemoresistance making the tumors increasingly sensitive to inhibition by anti-cancer agents [5]. This reversal is mechanistically achieved when melatonin upregulates the SiRT3/FOXO3a/PDH axis and also due to its inhibition of hypoxia inducible factor 1α (HIF-1α) which in turn reduces that activity of the enzyme pyruvate dehydrogenase kinase (PDK) [5].  This results in the disinhibition of PDH causing the re-establishment of acetyl CoA production thereby restoring intramitochondrial melatonin production and OXPHOS.