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

0582771 - FGÚ 2025 RIV US eng J - Journal Article
Chiang, A. C. Y. - Ježek, J. - Mu, P. - Di, Y. - Klucnika, A. - Jabůrek, Martin - Ježek, Petr - Ma, H.
Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.
Nature Communications. Roč. 15, č. 1 (2024), č. článku 611. E-ISSN 2041-1723
R&D Projects: GA ČR(CZ) GA22-17173S; GA ČR(CZ) GA21-01205S
Institutional support: RVO:67985823
Keywords : mitochondria * eukaryote * genetic interaction
OECD category: Biochemistry and molecular biology
Impact factor: 16.6, year: 2022
Method of publishing: Open access
https://doi.org/10.1038/s41467-024-44964-2

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.
Permanent Link: https://hdl.handle.net/11104/0351176