Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with noFxnexpression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmthas not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127Vand KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmtwere only identified in FxnG127Vhearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.Summary statementThe mitochondrial integrated stress response in the heart of a Friedreich Ataxia mouse model is surprisingly mild, despite a severe decrease in frataxin levels below 1% of normal.