MELATONIN AND PATHOLOGICAL CELL INTERACTIONS: MITOCHONDRIAL GLUCOSE PROCESSING IN CANCER CELLS

RUSSEL J. REITER; RAMASWAMY SHARMA; SERGIO ROSALES-CORRAL; WALTER MANUCHA; LUIZ GUSTAVO DE ALMEIDA CHUFFA; DEBORA APARECIDA PIRES DE CAMPOS ZUCCARI

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Lugar: Basel; Año: 2021 vol. 22 p. 1 - 22

1422-0067

Melatonin, a well-known secretory product of the vertebrate pineal gland, is synthesized and released into the cerebrospinal fluid and blood exclusively at night. This circadian melatonin rhythm regulates clock genes in the master circadian oscillator, the suprachiasmatic nucleus, and peripheral oscillators in all cells. These effects, like many others, are likely mediated by specific melatonin membrane receptors. Invertebrates, unicells, and plants also produce melatonin, proving that melatonin is not uniquely pineal in origin. Since it is now probable that melatonin is produced in the mitochondria of all cells, even in vertebrates, the amount of melatonin produced by the pineal gland is estimated to be less than 5% of the total melatonin synthesized. Mitochondria melatonin levels are much higher than in another subcellular organelle, and its levels do not exhibit a circadian rhythm. Mitochondria-derived melatonin has several critical molecular actions in all cells, some of which are likely receptor-independent. One significant effect of melatonin within cells is its ability to influence the glucose metabolism pathway. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate, the end product of glucose metabolism in normal cells, are excluded from the mitochondria such that it remains in the cytosol where it is metabolized lactate. The entrance of pyruvate into the mitochondria of normal cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA), which supports the tricarboxylic acid cycle and oxidative phosphorylation. The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA. This also is highly relevant to mitochondrial melatonin synthesis since acetyl-CoA is a required substrate in the synthetic melatonin pathway. PDH is inhibited during aerobic glycolysis and in cases where the intracellular microenvironment becomes hypoxic; in both these situations, the deficiency of acetyl-CoA prevents mitochondrial melatonin synthesis. If 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 circulating melatonin at night); in that case, the pathological cells convert to a more normal phenotype and support pyruvate transport into the mitochondria, thereby re-establishing healthier metabolic physiology.