Acute 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 cluster...

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Bibliographic Details
Published in:Disease models & mechanisms 2023-05, Vol.16 (5)
Main Authors: Cotticelli, M Grazia, Xia, Shujuan, Truitt, Rachel, Doliba, Nicolai M, Rozo, Andrea V, Tobias, John W, Lee, Taehee, Chen, Justin, Napierala, Jill S, Napierala, Marek, Yang, Wenli, Wilson, Robert B
Format: Article
Language:English
Subjects:
cardiomyopathy
DNA, Mitochondrial - metabolism
Frataxin
friedreich ataxia
Friedreich Ataxia - genetics
Friedreich Ataxia - metabolism
Humans
Induced Pluripotent Stem Cells - metabolism
innate immunity
interferon
Interferon Type I - metabolism
Iron - metabolism
Iron-Binding Proteins - genetics
Iron-Binding Proteins - metabolism
Mitochondrial Proteins - metabolism
mtdna
Myocytes, Cardiac - metabolism
Nucleotidyltransferases - metabolism
Sulfur - metabolism
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Summary: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.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.049497