Translational error in mice increases with ageing in an organ-dependent manner
Abstract The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57203-z |
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| author | Erik C. Böttger Harshitha Santhosh Kumar Adrian Steiner Emmanuel Sotirakis Kader Thiam Patricia Isnard Petit Petra Seebeck David P. Wolfer Dimitri Shcherbakov Rashid Akbergenov |
| author_facet | Erik C. Böttger Harshitha Santhosh Kumar Adrian Steiner Emmanuel Sotirakis Kader Thiam Patricia Isnard Petit Petra Seebeck David P. Wolfer Dimitri Shcherbakov Rashid Akbergenov |
| author_sort | Erik C. Böttger |
| collection | DOAJ |
| description | Abstract The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due to codon-anticodon mispairing than missense amino acid incorporation. Subsequently, we developed knock-in mice for in-vivo detection of stop-codon readthrough using a gain-of-function Kat2-TGA-Fluc readthrough reporter which combines fluorescent and sensitive bioluminescent imaging techniques. We followed expression of reporter proteins in-vivo over time, and assessed Kat2 and Fluc expression in tissue extracts and by whole organ ex-vivo imaging. Collectively, our results provide evidence for an organ-dependent, age-related increase in translational error: stop-codon readthrough increases with age in muscle (+ 75%, p < 0.001) and brain (+ 50%, p < 0.01), but not in liver (p > 0.5). Together with recent data demonstrating premature ageing in mice with an error-prone ram mutation, our findings highlight age-related decline of translation fidelity as a possible contributor to ageing. |
| format | Article |
| id | doaj-art-dc79bb1a66334ff68c3c1cc102b48ef8 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-dc79bb1a66334ff68c3c1cc102b48ef82025-08-20T02:16:34ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-57203-zTranslational error in mice increases with ageing in an organ-dependent mannerErik C. Böttger0Harshitha Santhosh Kumar1Adrian Steiner2Emmanuel Sotirakis3Kader Thiam4Patricia Isnard Petit5Petra Seebeck6David P. Wolfer7Dimitri Shcherbakov8Rashid Akbergenov9Institut für Medizinische Mikrobiologie, Universität ZürichInstitut für Medizinische Mikrobiologie, Universität ZürichAnatomisches Institut, Universität Zürich, and Institut für Bewegungswissenschaften und Sport, ETH ZürichgenOway, F-69362genOway, F-69362genOway, F-69362Zurich Integrative Rodent Physiology (ZIRP), University of ZurichAnatomisches Institut, Universität Zürich, and Institut für Bewegungswissenschaften und Sport, ETH ZürichInstitut für Medizinische Mikrobiologie, Universität ZürichInstitut für Medizinische Mikrobiologie, Universität ZürichAbstract The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due to codon-anticodon mispairing than missense amino acid incorporation. Subsequently, we developed knock-in mice for in-vivo detection of stop-codon readthrough using a gain-of-function Kat2-TGA-Fluc readthrough reporter which combines fluorescent and sensitive bioluminescent imaging techniques. We followed expression of reporter proteins in-vivo over time, and assessed Kat2 and Fluc expression in tissue extracts and by whole organ ex-vivo imaging. Collectively, our results provide evidence for an organ-dependent, age-related increase in translational error: stop-codon readthrough increases with age in muscle (+ 75%, p < 0.001) and brain (+ 50%, p < 0.01), but not in liver (p > 0.5). Together with recent data demonstrating premature ageing in mice with an error-prone ram mutation, our findings highlight age-related decline of translation fidelity as a possible contributor to ageing.https://doi.org/10.1038/s41467-025-57203-z |
| spellingShingle | Erik C. Böttger Harshitha Santhosh Kumar Adrian Steiner Emmanuel Sotirakis Kader Thiam Patricia Isnard Petit Petra Seebeck David P. Wolfer Dimitri Shcherbakov Rashid Akbergenov Translational error in mice increases with ageing in an organ-dependent manner Nature Communications |
| title | Translational error in mice increases with ageing in an organ-dependent manner |
| title_full | Translational error in mice increases with ageing in an organ-dependent manner |
| title_fullStr | Translational error in mice increases with ageing in an organ-dependent manner |
| title_full_unstemmed | Translational error in mice increases with ageing in an organ-dependent manner |
| title_short | Translational error in mice increases with ageing in an organ-dependent manner |
| title_sort | translational error in mice increases with ageing in an organ dependent manner |
| url | https://doi.org/10.1038/s41467-025-57203-z |
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