Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

Abstract

Friedreichs ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron-sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood, though are expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at FXN levels 8 weeks with FXN levels < 20% of normal, TG hearts did not display overt hypertrophy and were in fact smaller; global protein translation was lower, while protein degradative pathways were unaltered. Cardiac contractility was maintained, likely due to preserved {beta}-oxidation, though oxidative phosphorylation capacity for pyruvate was lower. Bioenergetics alterations matched mitochondrial proteomics changes, including a non-uniform decrease in abundance of ISC-containing proteins. In parallel, both mTORC1 signaling and the integrated stress response (ISR) were activated. The lack of overt cardiac hypertrophy, consistent with lower global protein translation, suggests that ISR predominated over mTORC1 activation. Suppression of a major ATP demanding process could benefit the FXN-depleted heart, at least short term. Thus, the FXN-depleted heart may enter a protective state, not necessarily linked to a major energy deficit. Finally, we propose the model used here as a pre-clinical model of cardiomyopathy in FRDA.