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. 2012 Dec 11;109(50):20590-5.
doi: 10.1073/pnas.1215349109. Epub 2012 Nov 20.

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

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

Megan Whitnall et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Dietary Fe supplementation (A) does not significantly rescue weight loss in mutant mice, but (B) significantly limits cardiac hypertrophy. Frataxin deficiency in the mutant heart and skeletal muscle leads to Fe loading in the (C) heart, (D) liver, (E) spleen, and (F) kidney. WT and mutants were fed a normal (0.02% Fe/kg) or high (2.00% Fe/kg) Fe diet from 4.5 to 8.5 wk of age. Results in A and B are mean ± SEM (n = 30–38 mice); (CF) are mean ± SEM (n = 24–30 mice). *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 2.
Fig. 2.
Frataxin deficiency in the heart prevents the normal physiological response to dietary Fe loading in (A) mutant heart and (B) causes systemic alterations to Fe-metabolism–related proteins in the mutant liver. Westerns are typical experiments and densitometry is mean ± SD (three to five experiments). *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 3.
Fig. 3.
Native size-exclusion chromatography of cytosolic and stromal mitochondrial membrane (SMM) fractions shows marked alterations exist in 59Fe distribution in the mutant heart relative to WT heart. Total 59Fe in the mutant SMM is only recovered upon treatment of the lysate with DFO. (A) cytosolic and (B) SMM fractions. Results are typical from three experiments.
Fig. 4.
Fig. 4.
In 9-wk-old mutant heart, Fe accumulates as aggregates, markedly different from mammalian ferritin found in mutant liver. TEM micrographs at (i) low and (ii) high magnification. (A) Mutant liver, showing isolated ferritin (arrows and Inset). (B) Mutant heart, Fe in smaller aggregates (Inset). Scale bars in A and B, (i) 100 nm and (ii) 25 nm; Inset, 6 nm. (C) Mössbauer spectra of 9-wk-old mutant tissues at 5 K: (i) liver spectrum, typical of mammalian ferritin and (ii) heart spectrum, Fe in a form different from mammalian ferritin. Solid lines are fits of doublets and sextets, with dotted and dashed lines representing sextet and doublet subcomponents of the fit for the liver spectrum. (D) At 9 wk old, Fe in mutant liver occurs as ferritin as shown by the in-phase susceptibility peak at ∼13 K, whereas no such peak is found in mutant hearts. Each experimental group represents n = 4–10 mice.

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