Revitalizing the neuronal powerhouse: therapeutic approaches for mitochondrial repair in neural dysfunction

Mitochondrial dysfunction is a significant contributor to neurodegeneration, impacting neuronal health and function across various neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. This review explores therapeutic strategies focused on mitochondrial rejuvenation, encompassing small molecule and metabolic modulation, mitochondrial augmentation therapies, and neuromodulatory approaches. Promising interventions include nicotinamide adenine dinucleotide boosters, antioxidants, and mitochondrial biogenesis activators that enhance energy metabolism and reduce oxidative stress. Stem cell-mediated mitochondrial transfer, isolated mitochondrial transplantation, and extracellular vesicle-based delivery represent innovative augmentation therapies aimed at restoring mitochondrial function. Additionally, red and near-infrared photobiomodulation alongside electrical and chemical neuromodulation is examined for its potential to enhance mitochondrial efficacy safely. The review also discusses translational barriers, including delivery challenges, timing of interventions, compatibility in donor-host integration, and the need for standardized functional assessments. Finally, clinical prospects highlight the importance of combining mitochondrial therapies with regenerative strategies and using engineering approaches for targeted and durable restoration of mitochondrial function, paving the way for enhanced outcomes in aging and neurodegenerative diseases.