Molecular Mechanisms of Mitochondrial Dysfunction in Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Advances

One of the main characteristics of severe neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) is mitochondrial dysfunction. These disorders cause progressive neuronal degeneration due to abnormalities in mitochondrial energy metabolism, redox regulation, calcium homeostasis, and quality control pathways. Mechanistically, the key pathogenic causes are altered electron transport chain activity, dysregulated mitochondrial dynamics (fission and fusion), impaired mitophagy, and increased formation of reactive oxygen species (ROS). Furthermore, mutations in proteins such as PINK1, Parkin, SOD1, TDP-43, and huntingtin worsen mitochondrial instability and interfere with mitochondrial-nucleus communication.This review provides a comprehensive analysis of mitochondrial dysfunction from a mechanistic perspective, highlighting disease-specific pathways and molecular targets. We evaluate current and emerging pharmacological strategies, including mitochondria-targeted antioxidants, biogenesis activators, calcium modulators, and mitophagy enhancers. In addition, we discuss drug delivery innovations, such as mitochondrial-penetrating peptides and nanoparticle systems, as well as the clinical progress and limitations of mitochondrial therapies.By integrating insights from molecular biology, pharmacology, and translational neuroscience, this review outlines the therapeutic potential of targeting mitochondria and offers perspectives on future drug discovery aimed at mitigating neurodegeneration through mitochondrial repair and protection. Keywords: Mitochondrial dysfunction, neurodegenerative diseases, PINK1, Parkinson’s disease, Alzheimer’s disease, SIRT3