Mitochondrial Dysfunction in Neurophysiology and Neurodegeneration: A Review

Abstract

       Mitochondrial dysfunction has emerged as a fundamental pathological mechanism underlying the onset and progression of numerous neurodegenerative disorders. Beyond their classical role in adenosine triphosphate (ATP) production, mitochondria regulate calcium homeostasis, redox signalling, apoptosis, mitophagy and neuroimmune responses, all of which are essential for maintaining neuronal integrity and synaptic function. Increasing evidence indicates that disturbances in oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA damage, impaired mitochondrial dynamics, defective mitophagy and chronic neuroinflammation collectively contribute to neuronal dysfunction and progressive neurodegeneration. These mitochondrial abnormalities have been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, highlighting mitochondria as attractive therapeutic targets.

   This review comprehensively summarizes the physiological functions of mitochondria in the nervous system and critically discusses the molecular mechanisms linking mitochondrial dysfunction with neurodegenerative diseases. Furthermore, recent advances in mitochondria-targeted therapeutic strategies, including mitochondria-targeted antioxidants (MitoQ), mitophagy activators (urolithin A), NAD⁺ augmentation therapies, mitochondrial biogenesis stimulators, metabolic interventions and emerging gene-based approaches, are reviewed with particular emphasis on their mechanisms of action and therapeutic potential. In addition, the review evaluates current challenges in clinical translation, including limited bioavailability, poor blood-brain barrier penetration, disease heterogeneity and the inconsistent outcomes of clinical trials despite encouraging preclinical evidence.

       Finally, current controversies, research gaps and future directions are highlighted to provide a critical perspective on the development of effective mitochondria-targeted therapies. A deeper understanding of mitochondrial biology, combined with advances in precision medicine, biomarker discovery and translational neuroscience, may facilitate the development of novel disease-modifying interventions capable of delaying neurodegeneration and improving long-term neurological outcomes.