{
  "abstract": "Friedreich ataxia (FRDA) is a metabolic disease with two faces. Loss of iron–sulfur cluster biogenesis disables oxidative phosphorylation, the Krebs cycle and the oxidation of fatty acids and ketone bodies, forcing tissues onto glycolysis and stranding lipid in droplets and as ceramide. The second aspect is on the supply side. A frataxin-deficient liver and adipose tissue deliver inadequate lipoprotein, fatty acid and ketone cargo to the heart, skeletal muscle and nervous system, the organs that depend most on imported fuel. Together, these lesions produce a cardiomyopathy that behaves like an engine out of fuel, a mixed diabetes of insulin deficiency and insulin resistance, low lean and bone mass and a redox-collapsed, ferroptosis-prone state. This review traces that logic from the cell to the organ to the whole body. The same map defines a compact panel of blood-based biomarkers, anchored on frataxin protein itself and extended by chain-resolved ceramides and by the succinate : fumarate, BHB : acetoacetate, NAD+ : NADH and GSH : GSSG ratios. It also nominates targets that do not require restoration of frataxin, including NRF2 activation, ferroptosis inhibition, NAD+ and sirtuin repletion, PPARgamma agonism, anaplerosis and ketone-based therapy. Reframing FRDA as a disorder of fuel logistics, rather than of fuel combustion alone, explains why a globally reduced protein produces a selective yet multisystem disease.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, University of Pennsylvania 1 , Philadelphia, PA, USA",
    "Department of Pharmacology, School of Medicine, University of Pennsylvania 2 , Philadelphia, PA, USA",
    "Department of Neurology, School of Medicine, University of Pennsylvania 3 , Philadelphia, PA, USA",
    "School of Medicine, University of Pennsylvania 4 , Philadelphia, PA, USA"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "David Lynch",
      "orcid": "0000-0001-7168-214X"
    },
    {
      "affs": [
        1
      ],
      "name": "Clementina Mesaros"
    },
    {
      "affs": [
        2
      ],
      "name": "Elizabeth Mercado Ayon"
    },
    {
      "affs": [
        3
      ],
      "name": "Yi Na Dong"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2t7swk122te0x.bib",
  "cited_by": 0,
  "doi": "10.1098/rsob.260221",
  "fulltext_url": "https://europepmc.org/articles/PMC13750920",
  "id": "2t7swk122te0x",
  "issns": [
    "2046-2441"
  ],
  "landing_url": "https://royalsocietypublishing.org/rsob/article/16/11/260221/484115/Metabolic-dysfunction-in-Friedreich",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": "https://royalsocietypublishing.org/rsob/article-pdf/doi/10.1098/rsob.260221/6176487/rsob.260221.pdf",
  "pmcid": "PMC13750920",
  "pmid": "43008814",
  "published": "2026-11-01",
  "publisher": "The Royal Society",
  "ris": "https://research.draconitic.com/paper/2t7swk122te0x.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T12:24:25Z",
      "native_id": "10.1098/rsob.260221",
      "source": "crossref",
      "url": "https://royalsocietypublishing.org/rsob/article/16/11/260221/484115/Metabolic-dysfunction-in-Friedreich"
    },
    {
      "first_seen": "2026-11-12T15:21:48Z",
      "native_id": "MED:43008814",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/43008814"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "journal-openalex:1312|Developmental Biology and Gene Regulation",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "issn:2046-2441",
      "subfield": "general"
    }
  ],
  "title": "Metabolic dysfunction in Friedreich ataxia",
  "title_text": "Metabolic dysfunction in Friedreich ataxia",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T03:20:44Z",
  "url": "https://research.draconitic.com/paper/2t7swk122te0x",
  "venue": "Open Biology",
  "versions": []
}