NDUFB4 is an accessory subunit of mitochondrial Complex I (NADH dehydrogenase) that functions in the electron transport chain by facilitating electron transfer from NADH to ubiquinone, contributing to oxidative phosphorylation and ATP synthesis. Beyond catalytic support, NDUFB4 plays a critical structural role in respiratory supercomplex assembly, particularly in forming the I1III2IV1 respirasome through interactions with Complex III subunit UQCRC1 1. Specific mutations in NDUFB4 residues (N24 and R30) impair respirasome formation and reduce mitochondrial respiratory flux and citric acid cycle metabolite levels, demonstrating functional significance for cellular bioenergetics 1. NDUFB4 expression correlates positively with maximal oxygen uptake and type 1 muscle fiber percentage, suggesting involvement in aerobic capacity and exercise adaptation 2. Disease relevance includes potential associations with hypertension susceptibility identified through Mendelian randomization analysis 3, and involvement in metabolic dysfunction associated with paclitaxel resistance in ovarian cancer 4 and energy stress-induced ferroptosis 5. NDUFB4 has been identified as a hub gene in collagen VI-related dystrophies and methylation-associated sarcopenia, linking it to muscle mass regulation 6, 7. Additionally, NDUFB4 upregulation occurs during malignant transformation of lung epithelial cells exposed to carcinogenic agents 8, suggesting broader relevance in cancer development.