Murdoch University Research Repository

Welcome to the Murdoch University Research Repository

The Murdoch University Research Repository is an open access digital collection of research
created by Murdoch University staff, researchers and postgraduate students.

Learn more

Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan

Richman, T.R., Ermer, J.A., Siira, S.J., Kuznetsova, I., Brosnan, C.A., Rossetti, G., Baker, J., Perks, K.L., Cserne Szappanos, H., Viola, H.M., Gray, N., Larance, M., Hool, L.C., Zuryn, S., Rackham, O. and Filipovska, A. (2021) Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan. Aging Cell . Early View.

[img]
Preview
Free to read: https://doi.org/10.1111/acel.13408
*No subscription required

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.

Item Type: Journal Article
Murdoch Affiliation(s): Australian National Phenome Center
Health Futures Institute
Publisher: Anatomical Society and John Wiley & Sons Ltd.
Copyright: © 2021 The Authors.
URI: http://researchrepository.murdoch.edu.au/id/eprint/61178
Item Control Page Item Control Page

Downloads

Downloads per month over past year