NDUFS4 is a nuclear-encoded accessory subunit of mitochondrial Complex I (NADH dehydrogenase), the first enzyme complex in the electron transport chain 1. While not directly involved in catalysis, NDUFS4 is essential for Complex I assembly and function in transferring electrons from NADH to ubiquinone, supporting oxidative phosphorylation and ATP generation 1. Mutations in NDUFS4 cause mitochondrial complex I deficiency, nuclear type 1 (MC1DN1), presenting as Leigh syndrome—a severe, early-onset encephalopathy with poor prognosis 1. NDUFS4 deficiency impairs cellular energy metabolism and triggers multiple secondary pathologies: it deactivates AMPK signaling, inhibiting lysosomal function and autophagy 2, increases reactive oxygen species accumulation and neuroinflammatory lipid droplet formation in glia 3, and causes lung tissue hyperoxia and sensitivity to oxygen toxicity through destabilization of iron-sulfur cluster proteins 4. Therapeutically, Ndufs4 knockout mouse models have demonstrated that chr5 hypoxia 5, small-molecule hypoxia mimetics 6, and exogenous healthy mitochondrial transfer 7 extend lifespan and ameliorate disease manifestations. Interestingly, selective NDUFS4 deficiency in cancer cells enhances antitumor immunity through acetyl-CoA accumulation and MHC class I upregulation 8.