Richman, Tara R. and Ermer, Judith A. and Siira, Stefan J. and Kuznetsova, Irina and Brosnan, Christopher A. and Rossetti, Giulia and Baker, Jessica and Perks, Kara L. and Cserne Szappanos, Henrietta and Viola, Helena M. and Gray, Nicola and Larance, Mark and Hool, Livia C. and Zuryn, Steven and Rackham, Oliver and Filipovska, Aleksandra (2021) Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan. Aging Cell, 20 (7). ISSN 1474-9718
Full text not available from this repository.Abstract
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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 30 Sep 2021 02:37 |
| Last Modified: | 30 Sep 2021 02:37 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1125 |
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