biostudies-literatureCotticelli MGChildren's Hospital of PhiladelphiaHamilton and Finneran FamiliesNIDDK NIH HHSChildren's Hospital of PhiladelphiaNINDS NIH HHSFriedreich's Ataxia Research AllianceFriedreich's Ataxia Research Alliancedmm049497https://www.ebi.ac.uk/biostudies/studies/S-EPMC9637271biostudies-literatureUnknown16(5)Friedreich ataxia, the most common hereditary ataxia, is a neuro- and cardio-degenerative disorder caused, in most cases, by decreased expression of the mitochondrial protein frataxin. Cardiomyopathy is the leading cause of premature death. Frataxin functions in the biogenesis of iron-sulfur clusters, which are prosthetic groups that are found in proteins involved in many biological processes. To study the changes associated with decreased frataxin in human cardiomyocytes, we developed a novel isogenic model by acutely knocking down frataxin, post-differentiation, in cardiomyocytes derived from induced pluripotent stem cells (iPSCs). Transcriptome analysis of four biological replicates identified severe mitochondrial dysfunction and a type I interferon response as the pathways most affected by frataxin knockdown. We confirmed that, in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.Disease models & mechanismsAcute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes activates a type I interferon response.PMC9637271P30 DK019525R01 NS124640Rozo AVNapierala JSYang WCotticelli MGWilson RBChen JDoliba NMXia STruitt RTobias JWLee TNapierala MfalseAcute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes activates a type I interferon response.Friedreich ataxia, the most common hereditary ataxia, is a neuro- and cardio-degenerative disorder caused, in most cases, by decreased expression of the mitochondrial protein frataxin. Cardiomyopathy is the leading cause of premature death. Frataxin functions in the biogenesis of iron-sulfur clusters, which are prosthetic groups that are found in proteins involved in many biological processes. To study the changes associated with decreased frataxin in human cardiomyocytes, we developed a novel isogenic model by acutely knocking down frataxin, post-differentiation, in cardiomyocytes derived from induced pluripotent stem cells (iPSCs). Transcriptome analysis of four biological replicates identified severe mitochondrial dysfunction and a type I interferon response as the pathways most affected by frataxin knockdown. We confirmed that, in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.2023-01-01T00:00:00Z2023 May2026-05-27T23:42:40.576Z2024-12-04T12:30:22.593ZS-EPMC96372713610785610.1242/dmm.049497