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

Chieh-Yin Chiang; Jan Jezek; Peiqiang Mu; Ying Di; Anna Klucnika; Martin Jaburek; Petr Jezek; Hansong Ma

doi:10.1038/s41467-024-44964-2

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

Chieh-Yin Chiang, Jan Jezek, Peiqiang Mu, Ying Di, Anna Klucnika, Martin Jaburek, Petr Jezek, Hansong Ma^*

^*Corresponding author for this work

Biosciences

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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.

Original language	English
Article number	611
Number of pages	11
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44964-2
Publication status	Published - 19 Jan 2024

Bibliographical note

Acknowledgements
We thank Professor Frank Jiggins from the University of Cambridge for providing the ten D. melanogaster stocks collected from the wild in the UK (Fig. 3c). We also would like to acknowledge the Gurdon Institute Core Facilities for their general support and the Metabolomics Core Facility at the Institute of Physiology of the Czech Academy of Sciences for conducting LC-MS-based lipidomics profiling. This work is funded by ERC Starting Grant 803852, Wellcome Trust Sir Henry Dale Fellowship 202269/Z/16/B, Philip Leverhulme Prize PLP-2020-063 and an EMBO Small Grant to H.M. The Gurdon Institute Core Facility is funded by Wellcome Trust grant 203144 and Cancer Research UK grant C6946/A24843. The Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, is funded by the Grant Agency of the Czech Republic grants 22-17173S and 21-01205S.

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10.1038/s41467-024-44964-2Licence: Creative Commons: Attribution (CC BY)

ChiangA2024TwoFinal published version, 2.19 MBLicence: Creative Commons: Attribution (CC BY)

Philip Leverhulme Prize Nomination: Nuclear Modulation of Mitochrondrial Mutant Phenotype.
Ma, H.
Leverhulme Trust
1/02/24 → 30/09/25
Project: Research
Mito-recombine - Homologous recombination and its application in manipulating animal mitochondrial DNA
Ma, H.
European Commission
1/05/23 → 31/08/24
Project: EU
The genetics of the Drosophila mitochondrial DNA and its influence on evolution and diesease
Ma, H.
THE WELLCOME TRUST
1/05/23 → 2/01/26
Project: Research

Cite this

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title = "Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality",

abstract = "Genetic screens have been used extensively to probe interactions betweennuclear genes and their impact on phenotypes. Probing interactions betweenmitochondrial genes and their phenotypic outcome, however, has not beenpossible due to a lack of tools to map the responsible polymorphisms. Here,using a toolkit we previously established in Drosophila, we isolate over 300recombinant 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 incytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemicalassays and phenotypic analyses, we show that the CoIII109 polymorphismmodulates cardiolipin binding to prevent complex IV instability caused by theCoIT300I mutation. This study demonstrates the feasibility of genetic interactionscreens in animal mitochondrial DNA. It unwraps the complex intra-genomicinterplays underlying disorders linked to mitochondrial DNA and how theyinfluence disease expression.",

author = "Chieh-Yin Chiang and Jan Jezek and Peiqiang Mu and Ying Di and Anna Klucnika and Martin Jaburek and Petr Jezek and Hansong Ma",

note = "Acknowledgements We thank Professor Frank Jiggins from the University of Cambridge for providing the ten D. melanogaster stocks collected from the wild in the UK (Fig. 3c). We also would like to acknowledge the Gurdon Institute Core Facilities for their general support and the Metabolomics Core Facility at the Institute of Physiology of the Czech Academy of Sciences for conducting LC-MS-based lipidomics profiling. This work is funded by ERC Starting Grant 803852, Wellcome Trust Sir Henry Dale Fellowship 202269/Z/16/B, Philip Leverhulme Prize PLP-2020-063 and an EMBO Small Grant to H.M. The Gurdon Institute Core Facility is funded by Wellcome Trust grant 203144 and Cancer Research UK grant C6946/A24843. The Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, is funded by the Grant Agency of the Czech Republic grants 22-17173S and 21-01205S.",

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AU - Chiang, Chieh-Yin

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AU - Klucnika, Anna

AU - Jaburek, Martin

AU - Jezek, Petr

AU - Ma, Hansong

N1 - Acknowledgements We thank Professor Frank Jiggins from the University of Cambridge for providing the ten D. melanogaster stocks collected from the wild in the UK (Fig. 3c). We also would like to acknowledge the Gurdon Institute Core Facilities for their general support and the Metabolomics Core Facility at the Institute of Physiology of the Czech Academy of Sciences for conducting LC-MS-based lipidomics profiling. This work is funded by ERC Starting Grant 803852, Wellcome Trust Sir Henry Dale Fellowship 202269/Z/16/B, Philip Leverhulme Prize PLP-2020-063 and an EMBO Small Grant to H.M. The Gurdon Institute Core Facility is funded by Wellcome Trust grant 203144 and Cancer Research UK grant C6946/A24843. The Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, is funded by the Grant Agency of the Czech Republic grants 22-17173S and 21-01205S.

PY - 2024/1/19

Y1 - 2024/1/19

N2 - Genetic screens have been used extensively to probe interactions betweennuclear genes and their impact on phenotypes. Probing interactions betweenmitochondrial genes and their phenotypic outcome, however, has not beenpossible due to a lack of tools to map the responsible polymorphisms. Here,using a toolkit we previously established in Drosophila, we isolate over 300recombinant 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 incytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemicalassays and phenotypic analyses, we show that the CoIII109 polymorphismmodulates cardiolipin binding to prevent complex IV instability caused by theCoIT300I mutation. This study demonstrates the feasibility of genetic interactionscreens in animal mitochondrial DNA. It unwraps the complex intra-genomicinterplays underlying disorders linked to mitochondrial DNA and how theyinfluence disease expression.

AB - Genetic screens have been used extensively to probe interactions betweennuclear genes and their impact on phenotypes. Probing interactions betweenmitochondrial genes and their phenotypic outcome, however, has not beenpossible due to a lack of tools to map the responsible polymorphisms. Here,using a toolkit we previously established in Drosophila, we isolate over 300recombinant 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 incytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemicalassays and phenotypic analyses, we show that the CoIII109 polymorphismmodulates cardiolipin binding to prevent complex IV instability caused by theCoIT300I mutation. This study demonstrates the feasibility of genetic interactionscreens in animal mitochondrial DNA. It unwraps the complex intra-genomicinterplays underlying disorders linked to mitochondrial DNA and how theyinfluence disease expression.

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

Abstract

Bibliographical note

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Projects

Philip Leverhulme Prize Nomination: Nuclear Modulation of Mitochrondrial Mutant Phenotype.

Mito-recombine - Homologous recombination and its application in manipulating animal mitochondrial DNA

The genetics of the Drosophila mitochondrial DNA and its influence on evolution and diesease

Cite this