How do mitochondrial dysfunction and oxidative stress contribute to disease?

Mitochondrial dysfunction causes disease through multiple mechanisms. Energy deficiency: tissues with high ATP demand (brain, heart, muscle) are most affected in respiratory chain defects. Oxidative stress: electron transport chain leakage generates ROS (superoxide, hydrogen peroxide); inadequate antioxidant defense causes macromolecular damage. Apoptosis: cytochrome c release triggers caspase activation. mtDNA vulnerability: proximity to ROS source, limited repair, leads to mutation accumulation with aging. Disease spectrum includes: primary mitochondrial diseases (MELAS, Leigh syndrome), neurodegenerative diseases (Parkinson's, Alzheimer's with mitochondrial involvement), metabolic syndrome, and aging. Therapeutic strategies: antioxidants (CoQ10, MitoQ), mitochondrial biogenesis enhancement (PGC1alpha activation), gene therapy for mtDNA mutations, and metabolic bypass of specific defects.