Impact of compound heterozygous SDHA variants on mitochondrial function in pediatric with neurological disease

Abstract

This study examines two rare compound heterozygous missense variants in the SDHA gene, c.1535G > A (p. R512Q) and c.1753C > T (p.R585W), identified in a pediatric patient presenting with neurological manifesta- tions, including epilepsy, developmental delay, and optic atrophy. The SDHA gene encodes a key component of succinate dehydrogenase (SDH), an essential enzyme complex at the intersection of two fundamental metabolic pathways: the Krebs cycle, and the mitochondrial respiratory chain (MRC). Patient-derived fibroblasts were used to evaluate the impact of the mutations on SDH activity and MRC as- sembly and function. The analysis revealed significant decreases in SDH activity and subunit levels, as well as impaired assembly. Additionally, complex I (CI) activity and CI-containing supercomplexes formation were also impaired, indicating more widespread mitochondrial dysfunction. Unexpectedly, basal and maximal respiration rates remained unchanged, though spare respiratory capacity was significantly reduced. These findings demonstrate the deleterious effects of the c.1535G > A and c.1753C > T variants, which had previously been associated with primary mitochondrial disorder (PMD) and tumors but had not been functionally validated until now