Daytime orexin and night-time melatonin regulation of mitochondria melatonin: roles in circadian oscillations systemically and centrally in breast cancer symptomatology

Abstract

     This article reviews the recent proposed model of Reiter and colleagues in this journal on the role of circadian, pineal gland-derived melatonin in driving mitochondria melatonin production in the pathoetiology and pathophysiology of breast cancers. This uptake of melatonin is proposed to inhibit pyruvate dehydrogenase kinase, thereby increasing the production of acetyl-CoA from pyruvate, with acetyl-CoA being a necessary co-factor for the initiation of the melatonergic pathway within mitochondria. Consequently, this proposed model suggests that a circadian shift in metabolic regulation occurs in breast cancers, from daytime cytosolic glycolysis to a night-time, melatonin-driven mitochondria oxidative phosphorylation, with relevance to the early pathoetiology of breast cancers. This has a number of consequences and links well to wider breast cancer data showing a pathophysiological role for the aryl hydrocarbon receptor, cytochrome P450 (CYP)1B1, 14-3-3 protein, and microRNAs. The current article overviews such data in the context of pineal gland-derived melatonin's circadian regulation of the mitochondria melatonergic pathways in breast cancer cells as proposed by Reiter and colleagues, suggesting that daytime, wake promoting orexin and stress-induced gut dysregulation contribute to mitochondria dysfunction in wider breast cancer symptomatology.