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

M. Whitnall, Y.S. Rahmanto, M. Huang, F. Saletta, H. Lok, Lucia Gutierrez-Marruedo, F. Lazaro, Adam Fleming, Tim St Pierre, M. Mikhael, P. Ponka, R. Richardson

    Research output: Contribution to journalArticle

    66 Citations (Scopus)


    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
    Pages (from-to)N/A
    Issue number50
    Publication statusPublished - 11 Dec 2012

    Fingerprint Dive into the research topics of 'Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia'. Together they form a unique fingerprint.

    Cite this