A novel NDUFS1 missense variant associated with optic atrophy and mitochondrial dysfunction

This study identified two compound heterozygous variants in the NDUFS1 gene in a patient presenting with optic atrophy including the known variant c.64C>T p.(R22X) and a novel variant c.404G>A p.(G135D). The Ndufs1^G135D/- mouse model exhibited reduced Ndufs1 expression, impaired optic nerve function and thinning of the ganglion cell complex/retinal thickness ratio. Structural and interaction analyses indicated the G135D variant located within the Fe-S cluster domain of NDUFS1, disrupted its interaction with NDUFV1, leading to protein instability and aberrant mitochondrial localization. Functional studies using NDUFS1 knockout HEK293 cells showed increased ROS, decreased mitochondrial membrane potential, reduced NAD⁺/NADH ratio, impaired complex I activity, decreased ATP production and defective oxidative phosphorylation. Mitochondrial dysfunction was not fully rescued by the G135D mutant protein. Collectively, the G135D variant was associated with impaired complex I-mediated electron transfer and mitochondrial dysfunction, providing insights into the pathogenesis of optic atrophy.