Mitochondrial mistranslation is modulated by metabolic stress

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 using mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. We find that while, metabolically both mutations are beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance they cause tissue specific defects when placed on a high fat diet. In contrast to the effect of the mutations on a normal diet the Mrps12ha/ha mice show more pronounced phenotypic and molecular defects as a result of the slow, accurate nature of their protein synthesis. While the Mrps12ep/ep mice accumulate more fat, exhibit larger vacuoles in the liver and lose glucose tolerance, the Mrps12ha/ha mice develop severe hypertrophic cardiomyopathy and hypoxia due to the stress of the diet, showing that benefit or detriment of error-prone and hyper-accurate protein synthesis in mitochondria is dependent on tissue and environmental conditions.