The Molecular and Cellular Mechanisms of Melatonin: From Physiological Actions to Clinical Applications in...

Melatonin has evolved from its classical role as a pineal-derived circadian regulator to a molecule increasingly recognized for its mitochondrial and cytoprotective functions. This review examines the molecular mechanisms and translational implications of melatonin within a mitochondria-centered framework, with particular emphasis on reproductive medicine. Available evidence suggests that melatonin may influence mitochondrial quality control (MQC) through multiple interconnected processes, including ROS regulation, mitochondrial dynamics, mitophagy, biogenesis, and mitochondrial inflammatory signaling. In mitochondria, melatonin can attenuate electron transport chain-derived oxidative stress through direct radical-scavenging reactions, antioxidant metabolite formation, and indirect activation of endogenous antioxidant systems. Experimental studies further suggest that melatonin may modulate Drp1-mediated fission, OPA1- and Mfn1/2-associated fusion, PINK1/Parkin-mediated mitophagy, and SIRT1/PGC-1α-related mitochondrial biogenesis. In reproductive medicine, melatonin has been investigated as a potential adjunctive strategy in assisted reproductive technology, endometriosis, and polycystic ovary syndrome. However, clinical evidence remains heterogeneous, and most human studies have evaluated reproductive or biochemical outcomes rather than direct MQC-related biomarkers. Therefore, although melatonin represents a promising mitochondria-targeted adjunct, standardized dosing strategies, tissue-level pharmacodynamic assessment, and validated mitochondrial biomarkers are needed to determine whether these mechanisms translate into reproducible clinical benefit.