Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

Abstract Friedreich’s ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction the main cause death. Yet pathogenesis, and, more generally, how heart adapts to FXN loss, remain poorly understood, though are expected be linked energy deficit. We modified transgenic (TG) mouse model inducible that permits phenotypic evaluation at different levels, and focused on substrate-specific bioenergetics stress signaling. When in TG was 17% normal, signaling were not from control. When, 8 weeks later, ~ 97% depleted heart, mass cardiomyocyte cross-sectional area less, without evidence fibrosis or apoptosis. mTORC1 activated, as integrated response, evidenced greater phosphorylation eIF2α relative total eIF2α, decreased translation. interpret these results suggest that, hearts, anabolic stimulus constrained phosphorylation. contractility maintained 97%-FXN-depleted possibly contributed unexpected preservation β-oxidation, pyruvate oxidation lower. Bioenergetics alterations matched changes proteome, including non-uniform decrease abundance ISC-containing proteins. Altogether, findings can suppress major ATP demanding process such translation, which, together with some could adaptive, least short term.