TY  - EJOU
AU  - Carloni, Silvia 
AU  - Nasoni, Maria Gemma 
AU  - Perrone, Serafina 
AU  - Bargagni, Erik 
AU  - Gentile, Carla 
AU  - Manucha, Walter 
AU  - Reiter, Russel J. 
AU  - Luchetti, Francesca 
AU  - Balduini, Walter 

TI  - Melatonin and Mitochondrial Function: Insights into Bioenergetics, Dynamics, and Gene Regulation
T2  - BIOCELL

PY  - 2026
VL  - 50
IS  - 2
SN  - 1667-5746

AB  - 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.
KW  - Melatonin; mitochondrial bioenergetics; mitochondrial dynamics; oxidative stress; tunneling nanotubes; mitokines

DO  - 10.32604/biocell.2025.073776