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

Mitochondria are central regulators of cellular energy metabolism, redox balance, and survival, and their dysfunction contributes to neurodegenerative, cardiovascular, and metabolic diseases, as well as aging. Beyond its role as a circadian hormone, melatonin is now recognized as a key modulator of mitochondrial physiology. This review provides an overview of the mechanisms by which melatonin can preserve mitochondrial function through multifaceted mechanisms. Experimental evidence shows that melatonin enhances the activity of electron transport chain (ETC) complexes, stabilizes the mitochondrial membrane potential (Δψ), and prevents cardiolipin (CL) peroxidation, thereby limiting permeability transition pore (mPTP) opening and cytochrome c release. Through its direct radical scavenging capacity and the upregulation of mitochondrial antioxidant defenses, melatonin protects against oxidative stress (OS) and preserves mitochondrial DNA integrity. Melatonin also regulates mitochondrial dynamics by promoting fusion, restraining excessive fission, and supporting quality control mechanisms such as mitophagy, unfolded protein response (UPR), and proteostasis. Moreover, melatonin influences mitochondrial biogenesis and intercellular communication through tunneling nanotubes (TNTs) and mitokine signaling. Thus, melatonin may represent a promising multifaceted therapeutic strategy for preserving mitochondrial homeostasis in a range of pathological conditions, including neurodegeneration and cardiovascular and metabolic diseases. However, a significant translational gap still remains between the promising preclinical data and the established clinical practice. Therefore, the aim of this review is to provide a comprehensive synthesis of current knowledge on the mechanisms through which melatonin modulates mitochondrial function and to discuss its potential therapeutic implications in neurodegenerative, cardiovascular, and metabolic diseases.