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Peer-reviewedCC BYCell Death and Disease

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model

  • Jarmon G. Lees1,2,3
  • Haoxiang Zhang4
  • Lebei Jiao4
  • Anne M. Kong4
  • Ren Jie Phang4
  • Li Li5,4
  • Nan Su5,4
  • Sebastian Bass-Stringer4
  • Hei-Yi H. Woo5,4
  • Anthony S Mukhtar4
  • Alice Pébay6,5
  • Mirella Dottori7
10 more authors
  • Louise A. Corben8,9
  • Martin Bruce Delatycki8,9,10
  • Roger E. Peverill11
  • Stephen Wilcox12
  • Jarny Choi4
  • Jeffrey M. Pullin4
  • Davis James McCarthy5,13,4
  • Jill S. Napierala14
  • Марек Напиерала14
  • Shiang Yong Lim15,16,17,18
18 affiliations
  1. 1Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia. [email protected]
  2. 2Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, Parkville, VIC, Australia. [email protected]
  3. 3St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia. [email protected]
  4. 4St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  5. 5Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia
  6. 6Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia
  7. 7School of Medical, Indigenous, and Health Sciences, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
  8. 8Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, VIC, Australia
  9. 9Department of Paediatrics, Melbourne University, Parkville, VIC, Australia
  10. 10Victorian Clinical Genetics Services, Parkville, VIC, Australia
  11. 11Victorian Heart Institute, Monash University, Clayton, VIC, Australia
  12. 12Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  13. 13Melbourne Integrative Genomics, University of Melbourne, Parkville, VIC, Australia
  14. 14Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
  15. 15Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia. [email protected]
  16. 16Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, Parkville, VIC, Australia. [email protected]
  17. 17National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore. [email protected]
  18. 18St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia. [email protected]
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Abstract

Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of MEG3 or PCDHGA10 in FRDA cardiomyocytes significantly reduced disease‑associated cell death without affecting FXN expression. Notably, PCDHGA10 silencing also normalized elevated mitochondrial reactive oxygen species, whereas MEG3 silencing did not, highlighting gene‑specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify MEG3 and PCDHGA10 as functionally relevant regulators of FRDA cardiomyocyte pathology.

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Cite

BibTeXRIS
BibTeX
@article{lees2026frataxin,
  title = {{Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model}},
  author = {Jarmon G. Lees and Haoxiang Zhang and Lebei Jiao and Anne M. Kong and Ren Jie Phang and Li Li and Nan Su and Sebastian Bass-Stringer and Hei-Yi H. Woo and Anthony S Mukhtar and Alice Pébay and Mirella Dottori and Louise A. Corben and Martin Bruce Delatycki and Roger E. Peverill and Stephen Wilcox and Jarny Choi and Jeffrey M. Pullin and Davis James McCarthy and Jill S. Napierala and Марек Напиерала and Shiang Yong Lim},
  journal = {Cell Death and Disease},
  year = {2026},
  month = jun,
  doi = {10.1038/s41419-026-09030-3},
  url = {https://doi.org/10.1038/s41419-026-09030-3},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model
AU  - Jarmon G. Lees
AU  - Haoxiang Zhang
AU  - Lebei Jiao
AU  - Anne M. Kong
AU  - Ren Jie Phang
AU  - Li Li
AU  - Nan Su
AU  - Sebastian Bass-Stringer
AU  - Hei-Yi H. Woo
AU  - Anthony S Mukhtar
AU  - Alice Pébay
AU  - Mirella Dottori
AU  - Louise A. Corben
AU  - Martin Bruce Delatycki
AU  - Roger E. Peverill
AU  - Stephen Wilcox
AU  - Jarny Choi
AU  - Jeffrey M. Pullin
AU  - Davis James McCarthy
AU  - Jill S. Napierala
AU  - Марек Напиерала
AU  - Shiang Yong Lim
PY  - 2026
DA  - 2026/06/23
JO  - Cell Death and Disease
DO  - 10.1038/s41419-026-09030-3
UR  - https://doi.org/10.1038/s41419-026-09030-3
AB  - Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of MEG3 or PCDHGA10 in FRDA cardiomyocytes significantly reduced disease‑associated cell death without affecting FXN expression. Notably, PCDHGA10 silencing also normalized elevated mitochondrial reactive oxygen species, whereas MEG3 silencing did not, highlighting gene‑specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify MEG3 and PCDHGA10 as functionally relevant regulators of FRDA cardiomyocyte pathology.
SN  - 2041-4889
ER  -