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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 (Mrps12(...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282274/ https://www.ncbi.nlm.nih.gov/pubmed/34096683 http://dx.doi.org/10.1111/acel.13408 |
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author | Richman, Tara R. Ermer, Judith A. Siira, Stefan J. Kuznetsova, Irina Brosnan, Christopher A. Rossetti, Giulia Baker, Jessica Perks, Kara L. Cserne Szappanos, Henrietta Viola, Helena M. Gray, Nicola Larance, Mark Hool, Livia C. Zuryn, Steven Rackham, Oliver Filipovska, Aleksandra |
author_facet | Richman, Tara R. Ermer, Judith A. Siira, Stefan J. Kuznetsova, Irina Brosnan, Christopher A. Rossetti, Giulia Baker, Jessica Perks, Kara L. Cserne Szappanos, Henrietta Viola, Helena M. Gray, Nicola Larance, Mark Hool, Livia C. Zuryn, Steven Rackham, Oliver Filipovska, Aleksandra |
author_sort | Richman, Tara R. |
collection | PubMed |
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 (Mrps12(ep) (/) (ep) ) or hyper‐accurate (Mrps12(ha) (/) (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, Mrps12(ep) (/) (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 Mrps12(ha) (/) (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. |
format | Online Article Text |
id | pubmed-8282274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82822742021-07-16 Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan Richman, Tara R. Ermer, Judith A. Siira, Stefan J. Kuznetsova, Irina Brosnan, Christopher A. Rossetti, Giulia Baker, Jessica Perks, Kara L. Cserne Szappanos, Henrietta Viola, Helena M. Gray, Nicola Larance, Mark Hool, Livia C. Zuryn, Steven Rackham, Oliver Filipovska, Aleksandra Aging Cell Original Articles 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 (Mrps12(ep) (/) (ep) ) or hyper‐accurate (Mrps12(ha) (/) (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, Mrps12(ep) (/) (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 Mrps12(ha) (/) (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. John Wiley and Sons Inc. 2021-06-07 2021-07 /pmc/articles/PMC8282274/ /pubmed/34096683 http://dx.doi.org/10.1111/acel.13408 Text en © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Richman, Tara R. Ermer, Judith A. Siira, Stefan J. Kuznetsova, Irina Brosnan, Christopher A. Rossetti, Giulia Baker, Jessica Perks, Kara L. Cserne Szappanos, Henrietta Viola, Helena M. Gray, Nicola Larance, Mark Hool, Livia C. Zuryn, Steven Rackham, Oliver Filipovska, Aleksandra 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 | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282274/ https://www.ncbi.nlm.nih.gov/pubmed/34096683 http://dx.doi.org/10.1111/acel.13408 |
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