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Linear mitochondrial DNA is rapidly degraded by components of the replication machinery

Author

Listed:
  • Viktoriya Peeva

    (University of Bonn)

  • Daniel Blei

    (University of Bonn)

  • Genevieve Trombly

    (University of Bonn)

  • Sarah Corsi

    (University of Bonn
    Newcastle University)

  • Maciej J. Szukszto

    (University of Cambridge)

  • Pedro Rebelo-Guiomar

    (University of Cambridge
    University of Porto)

  • Payam A. Gammage

    (University of Cambridge)

  • Alexei P. Kudin

    (University of Bonn)

  • Christian Becker

    (University of Cologne)

  • Janine Altmüller

    (University of Cologne
    University of Cologne)

  • Michal Minczuk

    (University of Cambridge)

  • Gábor Zsurka

    (University of Bonn
    University of Bonn)

  • Wolfram S. Kunz

    (University of Bonn
    University of Bonn)

Abstract

Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5′-3′exonuclease MGME1, elimination of the 3′-5′exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1.

Suggested Citation

  • Viktoriya Peeva & Daniel Blei & Genevieve Trombly & Sarah Corsi & Maciej J. Szukszto & Pedro Rebelo-Guiomar & Payam A. Gammage & Alexei P. Kudin & Christian Becker & Janine Altmüller & Michal Minczuk , 2018. "Linear mitochondrial DNA is rapidly degraded by components of the replication machinery," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04131-w
    DOI: 10.1038/s41467-018-04131-w
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    Cited by:

    1. 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.
    2. Yanan Li & Yonghua Wu & Ru Xu & Jialing Guo & Fenglei Quan & Yongyuan Zhang & Di Huang & Yiran Pei & Hua Gao & Wei Liu & Junjie Liu & Zhenzhong Zhang & Ruijie Deng & Jinjin Shi & Kaixiang Zhang, 2023. "In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Julian C. W. Willis & Pedro Silva-Pinheiro & Lily Widdup & Michal Minczuk & David R. Liu, 2022. "Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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