Projects per year
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.
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 |
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Article number | 611 |
Number of pages | 11 |
Journal | Nature Communications |
Volume | 15 |
Issue number | 1 |
DOIs | |
Publication status | Published - 19 Jan 2024 |
Bibliographical note
AcknowledgementsWe 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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Dive into the research topics of 'Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality'. Together they form a unique fingerprint.Projects
- 3 Active
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Philip Leverhulme Prize Nomination: Nuclear Modulation of Mitochrondrial Mutant Phenotype.
1/02/24 → 30/09/25
Project: Research
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The genetics of the Drosophila mitochondrial DNA and its influence on evolution and diesease
1/05/23 → 2/01/26
Project: Research