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Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality

Author

Listed:
  • Ason C. Y. Chiang

    (University of Birmingham
    Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge)

  • Jan Ježek

    (Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge
    Royal Free Hospital)

  • Peiqiang Mu

    (Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge
    South China Agricultural University)

  • Ying Di

    (Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge
    University of Cambridge)

  • Anna Klucnika

    (Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge
    Stevenage Bioscience Catalyst)

  • Martin Jabůrek

    (Institute of Physiology of the Czech Academy of Sciences)

  • Petr Ježek

    (Institute of Physiology of the Czech Academy of Sciences)

  • Hansong Ma

    (University of Birmingham
    Wellcome/Cancer Research UK Gurdon Institute
    University of Cambridge)

Abstract

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.

Suggested Citation

  • Ason C. Y. Chiang & Jan Ježek & Peiqiang Mu & Ying Di & Anna Klucnika & Martin Jabůrek & Petr Ježek & Hansong Ma, 2024. "Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44964-2
    DOI: 10.1038/s41467-024-44964-2
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    References listed on IDEAS

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    1. Pedro Silva-Pinheiro & Pavel A. Nash & Lindsey Van Haute & Christian D. Mutti & Keira Turner & Michal Minczuk, 2022. "In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Beverly Y. Mok & Marcos H. de Moraes & Jun Zeng & Dustin E. Bosch & Anna V. Kotrys & Aditya Raguram & FoSheng Hsu & Matthew C. Radey & S. Brook Peterson & Vamsi K. Mootha & Joseph D. Mougous & David R, 2020. "A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing," Nature, Nature, vol. 583(7817), pages 631-637, July.
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