Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans
Abstract Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Usi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61433-6 |
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| author | Iman Man Hu Marte Molenaars Yorrick R. J. Jaspers Bauke V. Schomakers Michel van Weeghel Amber Bakker Melanie Modder Joseph P. Dewulf Guido T. Bommer Arwen W. Gao Georges E. Janssens Riekelt H. Houtkooper |
| author_facet | Iman Man Hu Marte Molenaars Yorrick R. J. Jaspers Bauke V. Schomakers Michel van Weeghel Amber Bakker Melanie Modder Joseph P. Dewulf Guido T. Bommer Arwen W. Gao Georges E. Janssens Riekelt H. Houtkooper |
| author_sort | Iman Man Hu |
| collection | DOAJ |
| description | Abstract Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the “immuno-metabolic stress responses” in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses. |
| format | Article |
| id | doaj-art-8bf20dd1e23040d2b07c3b2c31da4a04 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8bf20dd1e23040d2b07c3b2c31da4a042025-08-20T03:45:31ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61433-6Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegansIman Man Hu0Marte Molenaars1Yorrick R. J. Jaspers2Bauke V. Schomakers3Michel van Weeghel4Amber Bakker5Melanie Modder6Joseph P. Dewulf7Guido T. Bommer8Arwen W. Gao9Georges E. Janssens10Riekelt H. Houtkooper11Laboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamDepartment of Pathology, New York University Grossman School of MedicineLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamDepartment of Biochemistry, de Duve Institute, UCLouvainDepartment of Biochemistry, de Duve Institute, UCLouvainLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamLaboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of AmsterdamAbstract Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the “immuno-metabolic stress responses” in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.https://doi.org/10.1038/s41467-025-61433-6 |
| spellingShingle | Iman Man Hu Marte Molenaars Yorrick R. J. Jaspers Bauke V. Schomakers Michel van Weeghel Amber Bakker Melanie Modder Joseph P. Dewulf Guido T. Bommer Arwen W. Gao Georges E. Janssens Riekelt H. Houtkooper Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans Nature Communications |
| title | Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans |
| title_full | Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans |
| title_fullStr | Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans |
| title_full_unstemmed | Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans |
| title_short | Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans |
| title_sort | immuno metabolic stress responses control longevity from mitochondrial translation inhibition in c elegans |
| url | https://doi.org/10.1038/s41467-025-61433-6 |
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