Gene

Stop codon

Mitochondrial respiratory chain

Molecular biology

Biology

Cytosine

Mitochondrial disease

Uracil

Genetics

Mitochondrial DNA

DNA repair

mitochondrial fusion

Mitochondrion

Human mitochondrial genetics

NADH dehydrogenase

DNA glycosylase

Nature Communications

DddA-derived cytosine base editors (DdCBEs), composed of the split interbacterial toxin DddA tox , transcription activator-like effector (TALE), and uracil glycosylase inhibitor (UGI), enable targeted C-to-T base conversions in mitochondrial DNA (mtDNA). Here, we demonstrate highly efficient mtDNA editing in mouse embryos using custom-designed DdCBEs. We target the mitochondrial gene, MT-ND5 ( ND5 ), which encodes a subunit of NADH dehydrogenase that catalyzes NADH dehydration and electron transfer to ubiquinone, to obtain several mtDNA mutations, including m.G12918A associated with human mitochondrial diseases and m.C12336T that incorporates a premature stop codon, creating mitochondrial disease models in mice and demonstrating a potential for the treatment of mitochondrial disorders.

Mitochondrial DNA editing in mice with DddA-TALE fusion deaminases