Melatonin and Mitochondrial Function: Insights into Bioenergetics, Dynamics, and Gene Regulation

Abstract

Mitochondria are central hubs of cellular bioenergetics, redox signaling, and cell fate determination, and their dysfunction represents a hallmark of several diseases, including neurodegenerative, cardiovascular, and metabolic disorders, as well as aging. Melatonin, classically considered a circadian hormone, has recently been recognized as an endogenous modulator of mitochondrial physiology. This review provides a comprehensive overview of the mechanisms by which melatonin preserves mitochondrial function through multifaceted mechanisms. At the bioenergetic level, melatonin enhances the activity of electron transport chain (ETC) complexes, stabilizes the mitochondrial membrane potential (Δψ), and prevents cardiolipin (CL) peroxidation, thereby limiting the opening of the permeability transition pore (mPTP) and the release of cytochrome c. Its potent radical scavenging activity, together with the upregulation of mitochondrial antioxidant enzymes, counteracts oxidative stress (OS) and preserves mitochondrial DNA integrity. Melatonin also finely regulates mitochondrial dynamics by promoting fusion and inhibiting pathological fission, while sustaining quality control pathways, including mitophagy, unfolded protein response (UPR), and proteostasis. At the transcriptional level, melatonin modulates canonical regulators of mitochondrial biogenesis and gene expression, thereby promoting mitochondrial resilience under stress conditions. Emerging data also highlight melatonin´s role in intercellular mitochondrial trafficking via tunneling nanotubes (TNTs) and in the modulation of mitokine signaling, linking mitochondrial homeostasis to systemic adaptation. In summary, melatonin emerges as a multifaceted regulator of mitochondrial function and dynamics, with significant translational implications for diseases associated with mitochondrial impairment.