Mitochondrial genome editing reveals the impact of complex I heteroplasmic variants on human neurogenesis

Complex I heteroplasmic mtDNA variants introduced into NGN2-inducible human iPSCs reduce mitochondrial membrane potential in iNs and impair neuronal commitment at relatively low heteroplasmy.

• Why it matters: Linking specific mtDNA variants to human neuronal phenotypes is difficult because patient-derived cells can’t isolate single variants and mtDNA editing is challenging.
• What they did: Using DddA-derived cytosine base editor (DdCBE), the study engineered pathogenic heteroplasmic variants in MT-ND1 and MT-ND5 in Neurogenin 2 (NGN2)-inducible human induced pluripotent stem cells, then assessed off-target editing, heteroplasmy, and differentiation into iNs.
• The result: The edited iPSC lines showed low off-target editing and maintained similar heteroplasmy after subclonal isolation and neuronal differentiation; in iNs, the variants triggered transcriptional reprogramming consistent with impaired neural fate specification.

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