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

Author

Listed:
  • Jinchun Wu

    (Peking University)

  • Yang Liu

    (Peking University)

  • Liqiong Ou

    (Peking University)

  • Tingting Gan

    (Peking University
    Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies)

  • Zhengrong Zhangding

    (Peking University)

  • Shaopeng Yuan

    (Peking University)

  • Xinyi Liu

    (Peking University)

  • Mengzhu Liu

    (Peking University)

  • Jiasheng Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jianhang Yin

    (Peking University)

  • Changchang Xin

    (Peking University)

  • Ye Tian

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiazhi Hu

    (Peking University
    Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies)

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.

Suggested Citation

  • Jinchun Wu & Yang Liu & Liqiong Ou & Tingting Gan & Zhengrong Zhangding & Shaopeng Yuan & Xinyi Liu & Mengzhu Liu & Jiasheng Li & Jianhang Yin & Changchang Xin & Ye Tian & Jiazhi Hu, 2024. "Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53806-0
    DOI: 10.1038/s41467-024-53806-0
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