| NDUFB8 is an accessory subunit within the mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase), a large L-shaped assembly composed of core and supernumerary subunits that spans the inner mitochondrial membrane to facilitate electron transfer from NADH to ubiquinone while pumping protons into the intermembrane space. Positioned on the matrix-protruding hydrophilic arm near iron-sulfur clusters, NDUFB8 integrates into the peripheral arm structure, stabilizing the Q-module where ubiquinone reduction occurs and supporting the overall architecture essential for proton translocation pathways. The subunit participates directly in complex I biogenesis by coordinating assembly of the iron-sulfur (FeS) subcomplex, enabling sequential incorporation of FeS clusters that shuttle electrons along a chain from FMN to the Q-site, with its absence disrupting late-stage maturation and yielding enzymatically inactive complexes. Tyrosine nitration at NDUFB8 triggers a signaling cascade involving RIP1 and RIP3 kinases, shifting cellular fate from apoptosis to programmed necrosis through formation of the necrosome, which amplifies mitochondrial damage and reactive oxygen species release. It sustains oxidative phosphorylation efficiency in high-energy demand tissues such as the brain and muscle, where complex I activity couples nutrient oxidation to ATP synthesis and regulates metabolic flux under varying substrate availability. Pathogenic biallelic variants in NDUFB8 cause isolated complex I deficiency, presenting with Leigh-like encephalomyopathy characterized by basal ganglia lesions, hypotonia, and lactic acidosis due to impaired electron transport and energy failure. |
Lane 1: HCT116, Lane 2: SW480, Lane 3: RAW264.7, Lane 4: H-4-II-E
