NDUFS2 is a core subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), catalyzing electron transfer from NADH to ubiquinone during oxidative phosphorylation 1. It is essential for both Complex I catalytic activity and assembly 12. Beyond canonical bioenergetic functions, NDUFS2 serves as a critical redox-sensitive oxygen sensor in pulmonary vasculature, regulating hypoxic pulmonary vasoconstriction through mitochondrial ROS production 3. In the brain, NDUFS2 phosphorylation by PKA modulates memory formation via mitochondrial bioenergetic control 4, and Complex I disruption induces progressive parkinsonism with loss of dopaminergic phenotype 5. Mutations in NDUFS2 cause Leber-like hereditary optic neuropathy and Complex I deficiency, manifesting as Leigh syndrome spectrum with multi-system dysfunction 6. NDUFS2 knockout zebrafish exhibit severe neuromuscular deficits, growth impairment, and metabolic dysregulation affecting electron transport chain, TCA cycle, and fatty acid oxidation pathways 6. AGK maintains NDUFS2 function to prevent non-alcoholic fatty liver disease progression 7, while aberrant NDUFS2 alternative splicing via PTBP1 contributes to dilated cardiomyopathy pathogenesis, treatable with coenzyme Q10 8. These findings establish NDUFS2 as a multifunctional metabolic hub integrating cellular respiration, oxygen sensing, and organ-specific pathophysiology.