Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia

Megan Whitnall, Yohan Suryo Rahmanto, Michael L.H. Huang, Federica Saletta, Hiu Chuen Lok, Lucía Gutiérrez, Francisco J. Lázaro, Adam J. Fleming, Tim G. St. Pierre, Marc R. Mikhael, Prem Ponka, Des R. Richardson

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich ataxia (FA). This disease is due to decreased expression of the mitochondrial protein, frataxin, which leads to alterations in mitochondrial iron (Fe) metabolism. The identification of potentially toxic mitochondrial Fe deposits in FA suggests Fe plays a role in its pathogenesis. Studies using the muscle creatine kinase (MCK) conditional frataxin knockout mouse that mirrors the disease have demonstrated frataxin deletion alters cardiac Fe metabolism. Indeed, there are pronounced changes in Fe trafficking away from the cytosol to the mitochondrion, leading to a cytosolic Fe deficiency. Considering Fe deficiency can induce apoptosis and cell death, we examined the effect of dietary Fe supplementation, which led to body Fe loading and limited the cardiac hypertrophy in MCK mutants. Furthermore, this study indicates a unique effect of heart and skeletal muscle-specific frataxin deletion on systemic Fe metabolism. Namely, frataxin deletion induces a signaling mechanism to increase systemic Fe levels and Fe loading in tissues where frataxin expression is intact (i.e., liver, kidney, and spleen). Examining the mutant heart, native size-exclusion chromatography, transmission electron microscopy, Mössbauer spectroscopy, and magnetic susceptibility measurements demonstrated that in the absence of frataxin, mitochondria contained biomineral Fe aggregates, which were distinctly different from isolated mammalian ferritin molecules. These mitochondrial aggregates of Fe, phosphorus, and sulfur, probably contribute to the oxidative stress and pathology observed in the absence of frataxin.

Original languageEnglish (US)
Pages (from-to)20590-20595
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 11 2012
Externally publishedYes


  • Ferroportin 1
  • Heme oxygenase
  • Hemojuvelin
  • Transferrin receptor 1

ASJC Scopus subject areas

  • General


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