Open Access

REVIEW

Mitochondrial Stress, Melatonin, and Neurodegenerative Diseases: New Nanopharmacological Approaches

Virna Margarita Martín Giménez¹, SebastiáN GarcíA MenéNdez^2,3, Luiz Gustavo A. Chuffa⁴, Vinicius Augusto SimãO⁴, Russel J. Reiter⁵, Ramaswamy Sharma⁶, Walter Balduini⁷, Carla Gentile⁸, Walter Manucha^2,3,*

1 Instituto de Investigaciones en Ciencias Químicas, Facultad de Ciencias Químicas y Tecnológicas, Universidad Católica de Cuyo, San Juan, 5400, Argentina
2 Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Mendoza, 5500, Argentina
3 Departamento de Patología, Área de Farmacología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, 5500, Argentina
4 Department of Structural and Functional Biology, Institute of Biosciences, UNESP-São Paulo State University, P.O. Box 18618-689, Botucatu, São Paulo, 510, Brazil
5 Department of Cell Systems and Anatomy, Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
6 Applied Biomedical Sciences, School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX 78209, USA
7 Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, 61029, Italy
8 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, Bldg. 16, Palermo, 90128, Italy

* Corresponding Author: Walter Manucha. Email:

(This article belongs to the Special Issue: Melatonin and Mitochondria: Exploring New Frontiers)

BIOCELL 2025, 49(12), 2245-2282. https://doi.org/10.32604/biocell.2025.071830

Received 13 August 2025; Accepted 29 September 2025; Issue published 24 December 2025

Abstract

Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, which is closely linked to mitochondrial dysfunction. These pathologies involve a complex interplay of genetics, protein misfolding, and cellular stress, culminating in impaired energy metabolism, an increase in reactive oxygen species (ROS), and defective mitochondrial quality control. The accumulation of damaged mitochondria and dysregulation of pathways such as the Integrated Stress Response (ISR) are central to the pathogenesis of these conditions. This review explores the critical relationship between mitochondrial stress and neurodegeneration, highlighting the molecular mechanisms and biomarkers involved. It delves into the multifaceted role of melatonin as a potent neuroprotective agent. Melatonin, a lipophilic indoleamine, is produced both in the pineal gland and locally within mitochondria, where it exerts powerful antioxidant, anti-inflammatory, and anti-apoptotic effects. Its unique ability to neutralize multiple free radicals and its cascade-based antioxidant action make it superior to conventional antioxidants. Its mechanisms of action are discussed, including signaling pathway modulation and enhancement of the brain’s clearance system (the glymphatic system). Despite its potential, melatonin’s low bioavailability and rapid metabolism limit its therapeutic efficacy. In this context, nanopharmacology emerges as a promising strategy. Nanoparticles such as liposomes, polymers, and solid lipids can encapsulate melatonin and protect it from degradation, facilitating its transport across the blood-brain barrier. Preclinical evidence has shown that melatonin-loaded nanoparticles significantly improve cognitive function, reduce oxidative stress, and restore mitochondrial homeostasis in models of AD, PD, and ALS. In conclusion, the synergistic combination of melatonin and nanopharmacology offers a multimodal and highly targeted approach for mitigating mitochondrial dysfunction in NDs. While challenges remain in optimizing the formulation and safety of these nanocarriers, this combination represents a crucial frontier for developing more effective and specific treatments in the future.

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