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 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 different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

Friedreich's ataxia is an inherited disorder caused by depletion of frataxin (Fxn), a mitochondrial protein involved in iron-sulfur cluster biogenesis. Cardiac dysfunction is the main cause of death; pathogenesis remains poorly understood but is expected to be linked to an energy deficit. In mice with adult-onset Fxn loss, bioenergetics analysis of heart mitochondria revealed a time-and substrate-dependent decrease in oxidative phosphorylation (oxphos). Oxphos was lower with substrates that depend on Complex I and II, but preserved for lipid substrates, especially through electron entry into Complex III via the electron transfer flavoprotein dehydrogenase. This differential substrate vulnerability is consistent with the half-lives for mitochondrial proteins.Cardiac contractility was preserved, likely due to sustained β-oxidation. Yet, a stress response was stimulated, characterized by activated mTORC1 and the p-eIF2α/ATF4 axis. This study exposes an unrecognized mechanism that maintains oxphos in the Fxn-depleted heart. The stress response that nonetheless occurs suggests energy deficit-independent pathogenesis. KEYWORDSFrataxin; bioenergetics; β-oxidation; cardiac metabolism; mitochondrial disease; integrated stress response cardiac hypertrophy (Huang et al., 2013, Seznec, Simon et al., 2004, Stram, Wagner et al., 2017, Wagner, Pride et al., 2012, which is not easily explained by elevated peIF2α and an ensuing decrease in global translation. Taken together, the mitochondrial disease literature suggests that multiple signaling pathways can be altered to potentially drive phenotypes. Thus, in any given model, it would be useful to broadly understand disrupted signaling. A broader understanding could expand the possible therapeutic targets and also reveal if disease heterogeneity needs to be considered in the context of FRDA treatments. The CKM mouse model of Fxn loss has been useful because it exhibits severe cardiac dysfunction (Huang et al., 2013, Martin, Abraham et al., 2017, Seznec et al., 2004); indeed it has been used to demonstrate the potential of gene replacement therapy in the heart (Belbellaa, Reutenauer et al., 2019, Perdomini, Belbellaa et al., 2014). Yet, this model features complete depletion of Fxn from birth and thus might reflect a developmental response. Moreover, the model has a rapid time course, making it more challenging to disentangle causes from consequences of severe pathology. A recently developed model of adult-onset Fxn depletion (Chandran, Gao et al., 2017) has several advantages for the study of the pathogenesis of cardiomyopathy in FRDA: the model avoids a developmental context, and has a wider window of time without overt major cardiac pathology. We have used this model to investigate the progression of cardiac mitochondrial metabolism and nutrient and stress signaling changes with the goal of obtaining insight into the pathogenesis of Fxn loss in the heart, specifically with regard to the impact on energy metabolism and how changes in energy metabolism might drive pathology. RESUL...