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

Ason C. Y. Chiang, Jan Ježek, Peiqiang Mu, Ying Di, Anna Klucnika, Martin Jabůrek, Petr Ježek and Hansong Ma ()
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Ason C. Y. Chiang: University of Birmingham
Jan Ježek: Wellcome/Cancer Research UK Gurdon Institute
Peiqiang Mu: Wellcome/Cancer Research UK Gurdon Institute
Ying Di: Wellcome/Cancer Research UK Gurdon Institute
Anna Klucnika: Wellcome/Cancer Research UK Gurdon Institute
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

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44964-2

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