Acute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes activates a type I interferon response
| Autor: | M. Grazia Cotticelli, Shujuan Xia, Rachel Truitt, Nicolai M. Doliba, Andrea V. Rozo, John W. Tobias, Taehee Lee, Justin Chen, Jill S. Napierala, Marek Napierala, Wenli Yang, Robert B. Wilson |
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| Rok vydání: | 2022 |
| Předmět: |
Iron
Induced Pluripotent Stem Cells Neuroscience (miscellaneous) Medicine (miscellaneous) DNA Mitochondrial Nucleotidyltransferases General Biochemistry Genetics and Molecular Biology Mitochondrial Proteins Immunology and Microbiology (miscellaneous) Friedreich Ataxia Iron-Binding Proteins Interferon Type I Humans Myocytes Cardiac Sulfur |
| Zdroj: | Disease Models & Mechanisms. 16 |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.049497 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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