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Abstract
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
Highlights
Melatonin has long been known to be an endogenously produced anti-cancer agent [1,2,3,4,5,6,7,8]
Given that melatonin is present perhaps in all living organisms [77,78], only a small portion of which have a pineal gland, it is obvious that the indoleamine did not evolve as a pineal-related molecule nor is it solely derived from this organ even in vertebrates
Stabilization of hypoxia inducible factor-1α (HIF-1α) during aerobic glycolysis in cancer cells may be, in part, related to the loss of mitochondrial melatonin synthesis owing to its antioxidant activity, while reducing cytokine production and/or release [206,207,208,209]
Summary
Melatonin has long been known to be an endogenously produced anti-cancer agent [1,2,3,4,5,6,7,8]. Provide clear evidence that, at least in some, xenografted human cancers growing in immune-compromised rats display a different metabolic phenotype during the day than at night These studies documented that the tumors exhibited Warburg-type metabolism, a feature common to many solid tumors [28,30,31], during the day but abandoned it, in toto or in part, at night in favor of mitochondrial oxidative phosphorylation (miOXPHOS) [32,33]. This circadian metabolic cycle is under control of the endogenous blood melatonin rhythm, which switches the cancer cells from a pathological Warburg-type metabolism during the day to a healthier metabolic phenotype at night [27,34,35]. We summarize treatment paradigms of these diseases that may maximize the efficiency of melatonin in impacting these pathologies
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