Acute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes activates a type I interferon response

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalDisease models & mechanisms
Volume16
Issue number5
DOIs
StatePublished - May 1 2023

Keywords

  • Cardiomyopathy
  • Friedreich ataxia
  • Innate immunity
  • Interferon
  • mtDNA

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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