Abstract
Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.
Highlights
The glucometabolic reprogramming that occurs in many cancer cells, and in other diseased cells as well [1,2], shifts ATP production away from the mitochondria and into the cytosol; this can occur even when ample oxygen is available and is referred to as aerobic glycolysis or the Warburg effect [3,4]
We propose that melatonin’s ability to modulate glucose metabolism in pathological cells is a general mechanism by which it impacts the progression of a variety of diseases
When antioxidants were compared with melatonin at equimolar concentrations, they were not these antioxidants were compared with melatonin at equimolar concentrations, better than native melatonin and for some indices, they were less effective than melatonin they were not better than native melatonin and for someactions indices,mediated they were by lessthe effective in reducing the inflammatory and pro-oxidative administration than melatonin in reducing the inflammatory and pro-oxidative actions mediated by the of highly toxic bacterial endotoxins. The relevance of these findings extend beyond the administration of highly toxic bacterial endotoxins. The relevance of these findings extend anti-inflammatory and antioxidant properties of melatonin inasmuch as mitochondrial beyond the anti-inflammatory and antioxidant properties of melatonin inasmuch as mimetabolism is commonly disturbeddisturbed in cancerincells, e.g., thee.g., Warburg effect, which tochondrial metabolism is commonly cancer cells, the Warburg effect, melatonin has been shown reverse which melatonin hastobeen shown to reverse [69,84,85]
Summary
The glucometabolic reprogramming that occurs in many cancer cells, and in other diseased cells as well [1,2], shifts ATP production away from the mitochondria and into the cytosol; this can occur even when ample oxygen is available and is referred to as aerobic glycolysis or the Warburg effect [3,4]. Suofu et al [78] incubated purified mitochondria with deuterated serotonin and observed they produced deuterated melatonin and related indoles These studies, more than any others, provide compelling data for the mitochondrial synthesis in non-pineal cell mitochondria; this is consistent with the high levels of melatonin measured in hepatocyte and neural mitochondria as reported by Venegas et al [61] and with the speculation that all cells, which contain mitochondria produce melatonin. They document there are two pools of melatonin, one releases it into the circulation, and one which does not [23,68]. Which melatonin hastobeen shown to reverse [69,84,85]
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