Pleiotropic impact of the loss of complex II in the organization of the respiratory chain and the mitochondrial ultrastructure

Succinate dehydrogenase (SDH, mitochondrial complex II) connects the tricarboxylic acid cycle and oxidative phosphorylation, and its dysfunction is associated with a broad spectrum of human diseases. It comprises a catalytic SDHA subunit and the electron-transferring SDHB subunit, which transfers electrons to the membrane-embedded SDHC/SDHD module where ubiquinone reduction occurs. Recessive defects in SDHA cause early-onset mitochondrial and neurodegenerative disorders, whereas heterozygous mutations in SDHB predispose to tumor development. A distinctive feature of SDHB deficiency is the accumulation of a stable assembly intermediate (CII-low) containing flavinated SDHA, whose functional relevance remains largely unexplored. Despite extensive characterization of SDH-related metabolic alterations, its direct impact on mitochondrial respiration and respiratory chain architecture has remained insufficiently defined. To address this critical gap, we established human cellular models deficient in either SDHA or SDHB, enabling discrimination between complete loss of complex II and conditions marked by CII-low accumulation. We found that CII-low lacked uncoupled activity despite containing flavinated SDHA. In both models, the loss of complex II activity caused severe impairment of mitochondrial respiration and ATP production. These changes were accompanied by marked remodeling of the respiratory chain, with complex I being the most consistently affected complex, as shown by BN-PAGE and proteomic analyses. At the organelle level, SDH deficiency induced mitochondrial abnormalities, including reduced cristae density. The similarity between the two knockout models indicates that the presence of CII-low does not make a major contribution to the observed phenotypes. These findings indicate that SDH deficiency contributes to disease through disruption of mitochondrial respiratory chain organization and ultrastructure.