Journal article
Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Aging Cell, Vol.20(7), Art. e13408
2021
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 (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.
Details
- Title
- Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
- Authors/Creators
- T.R. Richman (Author/Creator) - The University of Western AustraliaJ.A. Ermer (Author/Creator) - The University of Western AustraliaS.J. Siira (Author/Creator) - The University of Western AustraliaI. Kuznetsova (Author/Creator) - The University of Western AustraliaC.A. Brosnan (Author/Creator) - The University of QueenslandG. Rossetti (Author/Creator) - Harry Perkins Institute of Medical ResearchJ. Baker (Author/Creator) - Harry Perkins Institute of Medical ResearchK.L. Perks (Author/Creator) - Harry Perkins Institute of Medical ResearchH. Cserne Szappanos (Author/Creator)H.M. Viola (Author/Creator) - The University of Western AustraliaN. Gray (Author/Creator) - Murdoch UniversityM. Larance (Author/Creator) - The University of SydneyL.C. Hool (Author/Creator) - The University of Western AustraliaS. Zuryn (Author/Creator) - The University of QueenslandO. Rackham (Author/Creator) - Harry Perkins Institute of Medical ResearchA. Filipovska (Author/Creator) - Harry Perkins Institute of Medical Research
- Publication Details
- Aging Cell, Vol.20(7), Art. e13408
- Publisher
- Anatomical Society and John Wiley & Sons Ltd.
- Identifiers
- 991005542803207891
- Copyright
- © 2021 The Authors.
- Murdoch Affiliation
- Australian National Phenome Centre; Health Futures Institute
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- Citation topics
- 2 Chemistry
- 2.170 Nucleic Acids Chemistry
- 2.170.185 RNA Translation Dynamics
- Web Of Science research areas
- Cell Biology
- Geriatrics & Gerontology
- ESI research areas
- Molecular Biology & Genetics