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Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Author

Listed:
  • Nikolay P. Kandul

    (California Institute of Technology)

  • Ting Zhang

    (Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles
    Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles)

  • Bruce A. Hay

    (California Institute of Technology)

  • Ming Guo

    (Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles
    Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles)

Abstract

Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which mutant mtDNA co-exists in cells with wild-type mtDNA. High frequencies of pathogenic mtDNA result in maternally inherited diseases; maternally and somatically acquired mutations also accumulate over time and contribute to diseases of ageing. Reducing heteroplasmy is therefore a therapeutic goal and in vivo models in post-mitotic tissues are needed to facilitate these studies. Here we describe a transgene-based model of a heteroplasmic lethal mtDNA deletion (mtDNAΔ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNAΔ. Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNAΔ levels. These results show that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved.

Suggested Citation

  • Nikolay P. Kandul & Ting Zhang & Bruce A. Hay & Ming Guo, 2016. "Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13100
    DOI: 10.1038/ncomms13100
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    Cited by:

    1. Chih-Yao Chung & Kritarth Singh & Vassilios N. Kotiadis & Gabriel E. Valdebenito & Jee Hwan Ahn & Emilie Topley & Joycelyn Tan & William D. Andrews & Benoit Bilanges & Robert D. S. Pitceathly & Gyorgy, 2021. "Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation," Nature Communications, Nature, vol. 12(1), pages 1-16, 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. Huan Yang & Caroline Sibilla & Raymond Liu & Jina Yun & Bruce A. Hay & Craig Blackstone & David C. Chan & Robert J. Harvey & Ming Guo, 2022. "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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