Bibliographic Details
| Title: |
Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster. |
| Authors: |
El Fissi, Najla, Rosenberger, Florian A., Chang, Kai, Wilhalm, Alissa, Barton-Owen, Tom, Hansen, Fynn M., Golder, Zoe, Alsina, David, Wedell, Anna, Mann, Matthias, Chinnery, Patrick F., Freyer, Christoph, Wredenberg, Anna |
| Source: |
Nature Communications; 12/23/2024, Vol. 15 Issue 1, p1-15, 15p |
| Subject Terms: |
CYTOLOGY, LIFE sciences, CELL physiology, GENETIC testing, DROSOPHILA melanogaster, HOMEOSTASIS |
| 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. Finding ways to compensate for mitochondrial dysfunction is essential. Here, the authors performed a genome-wide genetic screen to identify genes that mitigate the larvae lethal phenotype of a fruit fly model with mitochondrial dysfunction. [ABSTRACT FROM AUTHOR] |
|
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
