Neuronal Deficiency of Cytochrome c Oxidase Engineered by Mitochondrial DNA Editing Recapitulates Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is categorized into 10% familial and 90% sporadic cases. While the space of 10% familial ALS is crowded with mutations in many genes of diverse functions, most ALS-associated mutations could not faithfully recapitulate the disease phenotype in animal models. Remarkably, nearly half of sporadic ALS patients exhibit defective mitochondrial respiratory complex â…£ (Câ…£). To establish the causal role of defective Câ…£ in inducing ALS, we employed TALE-based mtDNA editing to mimic ALS-linked mutations in Câ…£ compared to other respiratory complexes in rat neurons and demonstrated that mutations exclusively introduced to mtDNA-encoded Câ…£ subunits are sufficient to cause a full spectrum of ALS-like phenotypes, including selective motor neuron loss, SOD1 overexpression and cytosolic TDP-43 aggregation. These findings reveal a broad basis for sporadic ALS, provide critical insights into the selective motor neuron vulnerability, and present a faithful animal model for advancing ALS therapy.