Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks

Jinchun Wu, Yang Liu, Liqiong Ou, Tingting Gan, Zhengrong Zhangding, Shaopeng Yuan, Xinyi Liu, Mengzhu Liu, Jiasheng Li, Jianhang Yin, Changchang Xin, Ye Tian and Jiazhi Hu ()
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Jinchun Wu: Peking University
Yang Liu: Peking University
Liqiong Ou: Peking University
Tingting Gan: Peking University
Zhengrong Zhangding: Peking University
Shaopeng Yuan: Peking University
Xinyi Liu: Peking University
Mengzhu Liu: Peking University
Jiasheng Li: Chinese Academy of Sciences
Jianhang Yin: Peking University
Changchang Xin: Peking University
Ye Tian: Chinese Academy of Sciences
Jiazhi Hu: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.

Date: 2024
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DOI: 10.1038/s41467-024-53806-0

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