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Here we explored how environmental stress in the form of a high\u2010fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error\u2010prone (<jats:italic>Mrps12<jats:sup>ep<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>ep<\/jats:sup><\/jats:italic>) or hyper\u2010accurate (<jats:italic>Mrps12<jats:sup>ha<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>ha<\/jats:sup><\/jats:italic>) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high\u2010fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue\u2010specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, <jats:italic>Mrps12<jats:sup>ep<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>ep<\/jats:sup><\/jats:italic> 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 <jats:italic>Mrps12<jats:sup>ha<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>ha<\/jats:sup><\/jats:italic> mice protected the liver from a high\u2010fat 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\u2010mitotic (heart) and highly proliferative (liver) tissues. We show trade\u2010offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue\u2010specific outcomes due to commonly encountered stressful environmental conditions or aging.<\/jats:p>","DOI":"10.1111\/acel.13408","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T19:37:28Z","timestamp":1623181048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan"],"prefix":"10.1111","volume":"20","author":[{"given":"Tara R.","family":"Richman","sequence":"first","affiliation":[{"name":"Harry Perkins Institute of Medical Research QEII Medical Centre Nedlands WA Australia"},{"name":"ARC Centre of Excellence in Synthetic Biology QEII Medical Centre Nedlands WA Australia"},{"name":"Centre for Medical Research QEII Medical Centre, The University of Western Australia 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