Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12e...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
WILEY
2021
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| Subjects: | |
| Online Access: | http://purl.org/au-research/grants/arc/DP180101656 http://hdl.handle.net/20.500.11937/90821 |
| _version_ | 1848765437966286848 |
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| author | Richman, T.R. Ermer, J.A. Siira, S.J. Kuznetsova, I. Brosnan, C.A. Rossetti, G. Baker, J. Perks, K.L. Cserne Szappanos, H. Viola, H.M. Gray, N. Larance, M. Hool, L.C. Zuryn, S. Rackham, Oliver Filipovska, A. |
| author_facet | Richman, T.R. Ermer, J.A. Siira, S.J. Kuznetsova, I. Brosnan, C.A. Rossetti, G. Baker, J. Perks, K.L. Cserne Szappanos, H. Viola, H.M. Gray, N. Larance, M. Hool, L.C. Zuryn, S. Rackham, Oliver Filipovska, A. |
| author_sort | Richman, T.R. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging. |
| first_indexed | 2025-11-14T11:35:15Z |
| format | Journal Article |
| id | curtin-20.500.11937-90821 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:35:15Z |
| publishDate | 2021 |
| publisher | WILEY |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-908212023-04-24T01:19:05Z Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan Richman, T.R. Ermer, J.A. Siira, S.J. Kuznetsova, I. Brosnan, C.A. Rossetti, G. Baker, J. Perks, K.L. Cserne Szappanos, H. Viola, H.M. Gray, N. Larance, M. Hool, L.C. Zuryn, S. Rackham, Oliver Filipovska, A. Science & Technology Life Sciences & Biomedicine Cell Biology Geriatrics & Gerontology ageing metabolism mitochondria protein synthesis SIRT3 Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging. 2021 Journal Article http://hdl.handle.net/20.500.11937/90821 10.1111/acel.13408 English http://purl.org/au-research/grants/arc/DP180101656 http://creativecommons.org/licenses/by/4.0/ WILEY fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Cell Biology Geriatrics & Gerontology ageing metabolism mitochondria protein synthesis SIRT3 Richman, T.R. Ermer, J.A. Siira, S.J. Kuznetsova, I. Brosnan, C.A. Rossetti, G. Baker, J. Perks, K.L. Cserne Szappanos, H. Viola, H.M. Gray, N. Larance, M. Hool, L.C. Zuryn, S. Rackham, Oliver Filipovska, A. Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title | Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title_full | Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title_fullStr | Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title_full_unstemmed | Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title_short | Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| title_sort | mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan |
| topic | Science & Technology Life Sciences & Biomedicine Cell Biology Geriatrics & Gerontology ageing metabolism mitochondria protein synthesis SIRT3 |
| url | http://purl.org/au-research/grants/arc/DP180101656 http://hdl.handle.net/20.500.11937/90821 |