Precise modelling of mitochondrial diseases using optimized mitoBEs

Xiaoxue Zhang, Xue Zhang, Jiwu Ren, Jiayi Li, Xiaoxu Wei, Ying Yu, Zongyi Yi () and Wensheng Wei ()
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Xiaoxue Zhang: Changping Laboratory
Xue Zhang: Changping Laboratory
Jiwu Ren: Changping Laboratory
Jiayi Li: Peking University
Xiaoxu Wei: Peking University
Ying Yu: Peking University
Zongyi Yi: Changping Laboratory
Wensheng Wei: Changping Laboratory

Nature, 2025, vol. 639, issue 8055, 735-745

Abstract: Abstract The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber’s hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.

Date: 2025
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DOI: 10.1038/s41586-024-08469-8

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