Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

Abstract Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and currently incurable. The lack effective models hampers our understanding the mechanisms underlying neuronal pathology LS. Using patient-derived induced pluripotent stem cells CRISPR/Cas9 engineering, we developed human model LS caused by mutations complex IV assembly gene SURF1 . Single-cell RNA-sequencing multi-omics analysis revealed compromised morphogenesis mutant neural cultures brain organoids. defects emerged at level progenitor (NPCs), which retained glycolytic proliferative state that failed to instruct morphogenesis. NPCs carrying I NDUFS4 recapitulated defects. augmentation PGC1A induction via bezafibrate treatment supported metabolic programming NPCs, leading restored Our findings provide mechanistic insights suggest potential interventional strategies for rare disease.