ArticleProceedings of the National Academy of Sciences of the United States of America2008
The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 118 citations in OpenAlex.
- Therapeutic activity of a hematopoietic stem cell-delivered cell-penetrating frataxin in Friedreich's ataxia models.Cell reports. Medicine · 2026Article
- Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.Mitochondrion · 2026Article
- Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis.iScience · 2026Article
- Recent developments in Friedreich's ataxia: a state-of-the-art review.Brain communications · 2026Review
- Alpha-lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia.Orphanet journal of rare diseases · 2025Article
- AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.Molecular therapy. Methods & clinical development · 2024Article
- A kinetic model of iron trafficking in growing Saccharomyces cerevisiae cells; applying mathematical methods to minimize the problem of sparse data and generate viable autoregulatory mechanisms.PLoS computational biology · 2023Article
- Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia.Human gene therapy · 2023Article
- Mitochondrial Iron Metabolism: The Crucial Actors in Diseases.Molecules (Basel, Switzerland) · 2022Review
- FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation.Neurology. Genetics · 2022Article
- Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations.Cellular and molecular life sciences : CMLS · 2022Article
- Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies.Redox biology · 2021Review
- Cysteine Deprivation Targets Ovarian Clear Cell CarcinomaAntioxidants & redox signaling · 2020Article
- Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion?Antioxidants (Basel, Switzerland) · 2020Review
- Article
- The role of mitochondrial labile iron in Friedreich's ataxia skin fibroblasts sensitivity to ultraviolet A.Metallomics : integrated biometal science · 2019Article
- The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis.Oxidative medicine and cellular longevity · 2019Review
- The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models.Frontiers in neuroscience · 2019Review
- Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?Pharmaceuticals (Basel, Switzerland) · 2018Review
- Identification of cardioprotective drugs by medium-scaleDisease models & mechanisms · 2018Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.
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