gene editing mitochondria briefs

Complex I heteroplasmy in MT-ND1 or MT-ND5 is enough to drop neuronal membrane potential and stall commitment

DddA-derived cytosine base editors (DdCBE) introduce pathogenic heteroplasmic variants of MT-ND1 or MT-ND5 into Neurogenin 2 (NGN2)-inducible human iPSCs with low off-target editing. Heteroplasmy holds through subclonal isolation and differentiation into induced neurons. The same Complex I variants barely change mitochondrial energy metabolism in undifferentiated iPSCs, yet they reduce mitochondrial membrane potential in induced neurons and drive a transcriptional program of impaired neuronal commitment, even at relatively low heteroplasmy.