Mitochondrial dynamics and neuronal death in neurodegenerative diseases

Neurodegenerative diseases like Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis, and Huntington’s disease are characterized by progressive neuronal loss, yet their molecular underpinnings remain incompletely understood. This article provides a comprehensive and integrative analysis of mitochondrial dynamics including fission, fusion, and transport and their role in neuronal survival and death, offering new insights into how their disruption drives neurodegeneration. Unlike prior reviews that focus on single diseases, this work highlights common mechanistic failures, including mitochondrial fragmentation, impaired energy metabolism, oxidative stress, defective mitophagy, and disrupted organelle crosstalk, while linking them to disease-specific hallmarks such as PINK1/Parkin pathway defects, amyloid β and tau toxicity, mutant SOD1 trafficking disturbances, and transcriptional dysregulation. The novelty of this review lies in its cross-disease perspective, unifying mitochondrial dysfunction across multiple neurodegenerative disorders and emphasizing the interplay of molecular regulators such as DRP1, MFN1/2, OPA1, PGC-1α, and SIRT proteins. In addition, it highlights emerging therapeutic approaches including small-molecule modulators, mitophagy enhancers, antioxidants, bioenergetic support and advanced gene or nanocarrier-based strategies, positioning mitochondrial dynamics as a promising therapeutic area. Finally, this article underscores the urgent need for reliable biomarkers and translational pathways, offering a progressive view of personalized mitochondrial medicine in neurodegeneration.