Function of intramitochondrial melatonin and its association with Warburg metabolism.

Warburg metabolism (aerobic glycolysis) is accompanied by high mitochondrial reactive oxygen species (ROS) generation from the electron transport chain; this is a "Hallmark of Cancer". The elevated ROS sustain the growth and proliferation of the cancer cells. Melatonin is a potent and functionally diverse free radical scavenger and antioxidant that is synthesized in the mitochondria of non-pathological cells and normally aids in keeping mitochondrial ROS levels low and in maintaining redox homeostasis. Because the glucose metabolite, pyruvate, does not enter mitochondria of Warburg metabolizing cells due to the inhibition of pyruvate dehydrogenase complex (PDH), acetyl coenzyme A production is diminished. Acetyl coenzyme A is a necessary co-substrate with serotonin for melatonin synthesis; thus, intramitochondrial melatonin levels become reduced in cancer cells. The hypothesis is that the depressed melatonin levels initiate aerobic glycolysis and allow the exaggerated ROS concentrations to go uncontested; the authors speculate that the elevated mtROS upregulates hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase (PDK) axis which inhibits PDH, thereby supporting cancer cell proliferation and stimulating cancer biomass. Exposing Warburg metabolizing cancer cells to melatonin elevates intramitochondrial melatonin, thereby reducing mtROS and concurrently interrupting aerobic glycolysis and inhibiting tumor cell proliferation. Mechanistically, higher mitochondrial melatonin levels by supplementation directly upregulates the sirtuin 3 (SIRT3)/FOXO/PDH axis, allowing pyruvate entry into mitochondria and enhancing intrinsic mitochondrial melatonin production as in non-pathological cells. Additionally, melatonin inhibits HIF1α, thereby decreasing PDK activity and disinhibiting PDH, so pyruvate enters mitochondria and is metabolized to acetyl coenzyme A, resulting in reversal of Warburg metabolism.