Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster
Abstract Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain c...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55559-2 |
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| author | Najla El Fissi Florian A. Rosenberger Kai Chang Alissa Wilhalm Tom Barton-Owen Fynn M. Hansen Zoe Golder David Alsina Anna Wedell Matthias Mann Patrick F. Chinnery Christoph Freyer Anna Wredenberg |
| author_facet | Najla El Fissi Florian A. Rosenberger Kai Chang Alissa Wilhalm Tom Barton-Owen Fynn M. Hansen Zoe Golder David Alsina Anna Wedell Matthias Mann Patrick F. Chinnery Christoph Freyer Anna Wredenberg |
| author_sort | Najla El Fissi |
| collection | DOAJ |
| description | Abstract Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention. |
| format | Article |
| id | doaj-art-3f7fc21ea23d431f83a462ffeccd4b16 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-3f7fc21ea23d431f83a462ffeccd4b162024-12-29T12:38:03ZengNature PortfolioNature Communications2041-17232024-12-0115111510.1038/s41467-024-55559-2Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogasterNajla El Fissi0Florian A. Rosenberger1Kai Chang2Alissa Wilhalm3Tom Barton-Owen4Fynn M. Hansen5Zoe Golder6David Alsina7Anna Wedell8Matthias Mann9Patrick F. Chinnery10Christoph Freyer11Anna Wredenberg12Department of Medical Biochemistry and Biophysics, Karolinska InstitutetProteomics and Signal Transduction, Max-Planck Institute of BiochemistryDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical CampusProteomics and Signal Transduction, Max-Planck Institute of BiochemistryDepartment of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical CampusDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetCentre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76Proteomics and Signal Transduction, Max-Planck Institute of BiochemistryDepartment of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical CampusDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetAbstract Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.https://doi.org/10.1038/s41467-024-55559-2 |
| spellingShingle | Najla El Fissi Florian A. Rosenberger Kai Chang Alissa Wilhalm Tom Barton-Owen Fynn M. Hansen Zoe Golder David Alsina Anna Wedell Matthias Mann Patrick F. Chinnery Christoph Freyer Anna Wredenberg Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster Nature Communications |
| title | Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster |
| title_full | Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster |
| title_fullStr | Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster |
| title_full_unstemmed | Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster |
| title_short | Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster |
| title_sort | preventing excessive autophagy protects from the pathology of mtdna mutations in drosophila melanogaster |
| url | https://doi.org/10.1038/s41467-024-55559-2 |
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