A mitochondrial long-chain fatty acid oxidation defect leads to tRNA uncharging and activation of the integrated stress response in the mouse heart.

Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact on cardiac metabolic signaling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signaling pathways such as the integrated stress response.