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

Silvia Carloni^1,*, Maria Gemma Nasoni¹, Serafina Perrone², Erik Bargagni¹, Carla Gentile³, Walter Manucha⁴, Russel J. Reiter⁵, Francesca Luchetti^1,*, Walter Balduini^1,*
1 Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, 61029, Italy
2 Department of Medicine and Surgery, University of Parma, Parma, 43125, Italy
3 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, 90128, Italy
4 Instituto de Medicina y Biologia Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Mendoza, 5500, Argentina
5 Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX 78229, USA
* Corresponding Author: Silvia Carloni. Email: email ; Francesca Luchetti. Email: email ; Walter Balduini. Email: email
(This article belongs to the Special Issue: Melatonin and Mitochondria: Exploring New Frontiers)

BIOCELL https://doi.org/10.32604/biocell.2025.073776

Received 25 September 2025; Accepted 12 November 2025; Published online 01 December 2025

Download PDF

Abstract

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.