{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia. jlees@svi.edu.au",
    "Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, Parkville, VIC, Australia. jlees@svi.edu.au",
    "St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia. jlees@svi.edu.au",
    "St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia",
    "Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia",
    "Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia",
    "School of Medical, Indigenous, and Health Sciences, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia",
    "Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, VIC, Australia",
    "Department of Paediatrics, Melbourne University, Parkville, VIC, Australia",
    "Victorian Clinical Genetics Services, Parkville, VIC, Australia",
    "Victorian Heart Institute, Monash University, Clayton, VIC, Australia",
    "Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia",
    "Melbourne Integrative Genomics, University of Melbourne, Parkville, VIC, Australia",
    "Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA",
    "Department of Medicine and Surgery, University of Melbourne, Parkville, VIC, Australia. mlim@svi.edu.au",
    "Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, Parkville, VIC, Australia. mlim@svi.edu.au",
    "National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore. mlim@svi.edu.au",
    "St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia. mlim@svi.edu.au"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jarmon G. Lees",
      "orcid": "0000-0002-9259-8657"
    },
    {
      "affs": [
        3
      ],
      "name": "Haoxiang Zhang",
      "orcid": "0000-0002-6302-0901"
    },
    {
      "affs": [
        3
      ],
      "name": "Lebei Jiao"
    },
    {
      "affs": [
        3
      ],
      "name": "Anne M. Kong",
      "orcid": "0009-0000-6634-0436"
    },
    {
      "affs": [
        3
      ],
      "name": "Ren Jie Phang",
      "orcid": "0000-0002-0283-328X"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Li Li"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Nan Su",
      "orcid": "0000-0002-9405-6018"
    },
    {
      "affs": [
        3
      ],
      "name": "Sebastian Bass-Stringer"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Hei-Yi H. Woo"
    },
    {
      "affs": [
        3
      ],
      "name": "Anthony S Mukhtar"
    },
    {
      "affs": [
        5,
        4
      ],
      "name": "Alice Pébay",
      "orcid": "0000-0002-7408-9453"
    },
    {
      "affs": [
        6
      ],
      "name": "Mirella Dottori",
      "orcid": "0000-0003-0598-4195"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Louise A. Corben",
      "orcid": "0000-0001-8767-4582"
    },
    {
      "affs": [
        7,
        8,
        9
      ],
      "name": "Martin Bruce Delatycki",
      "orcid": "0000-0002-8769-2569"
    },
    {
      "affs": [
        10
      ],
      "name": "Roger E. Peverill",
      "orcid": "0000-0002-3319-5356"
    },
    {
      "affs": [
        11
      ],
      "name": "Stephen Wilcox"
    },
    {
      "affs": [
        3
      ],
      "name": "Jarny Choi",
      "orcid": "0000-0002-7788-8867"
    },
    {
      "affs": [
        3
      ],
      "name": "Jeffrey M. Pullin",
      "orcid": "0000-0003-3651-5471"
    },
    {
      "affs": [
        4,
        12,
        3
      ],
      "name": "Davis James McCarthy",
      "orcid": "0000-0002-2218-6833"
    },
    {
      "affs": [
        13
      ],
      "name": "Jill S. Napierala",
      "orcid": "0000-0002-5141-0822"
    },
    {
      "affs": [
        13
      ],
      "name": "Марек Напиерала",
      "orcid": "0000-0002-9987-0641"
    },
    {
      "affs": [
        14,
        15,
        16,
        17
      ],
      "name": "Shiang Yong Lim",
      "orcid": "0000-0002-0442-3655"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0tdj85h2wbm7p.bib",
  "cited_by": 5,
  "doi": "10.1038/s41419-026-09030-3",
  "fulltext_url": null,
  "id": "0tdj85h2wbm7p",
  "issns": [
    "2041-4889"
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  "landing_url": "https://doi.org/10.1038/s41419-026-09030-3",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "2804|Genetic Neurodegenerative Diseases"
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  "pdf_url": "https://www.nature.com/articles/s41419-026-09030-3_reference.pdf",
  "pmcid": "PMC13538398",
  "pmid": "42331777",
  "published": "2026-06-23",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/0tdj85h2wbm7p.ris",
  "sources": [
    {
      "first_seen": "2026-11-13T13:21:09Z",
      "native_id": "W4413477838",
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      "url": "https://doi.org/10.1038/s41419-026-09030-3"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Genetic Neurodegenerative Diseases",
      "subfield": "neuroscience"
    }
  ],
  "title": "Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model",
  "title_text": "Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:09Z",
  "url": "https://research.draconitic.com/paper/0tdj85h2wbm7p",
  "venue": "Cell Death and Disease",
  "versions": []
}