Open AccessMitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Author(s) -
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
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13408
Subject(s) - biology , mitochondrion , endocrinology , translation (biology) , medicine , microbiology and biotechnology , gene , biochemistry , messenger rna
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.