TY - JOUR
T1 - Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia
AU - Whitnall, Megan
AU - Rahmanto, Yohan Suryo
AU - Huang, Michael L.H.
AU - Saletta, Federica
AU - Lok, Hiu Chuen
AU - Gutiérrez, Lucía
AU - Lázaro, Francisco J.
AU - Fleming, Adam J.
AU - St. Pierre, Tim G.
AU - Mikhael, Marc R.
AU - Ponka, Prem
AU - Richardson, Des R.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank H. Puccio and M. Koenig for MCK mice. This work was supported by the National Health and Medical Research Council, the Muscular Dystrophy Association, and the Canadian Institutes of Health Research.
Funding Information:
aDepartment of Pathology, University of Sydney, Sydney 2006, Australia; bInstituto de Ciencia de Materiales de Madrid/Consejo Superior de Investigaciones Científicas, Cantoblanco, 28049 Madrid, Spain; cSchool of Physics, University of Western Australia, Perth 6009, Australia; dDepartamento de Ciencia y Tecnología de Materiales y Fluidos, Universidad de Zaragoza, 50018 Zaragoza, Spain; and eLady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada H3T 1E2
Publisher Copyright:
© 2012, National Academy of Sciences. All rights reserved.
PY - 2012/12/11
Y1 - 2012/12/11
N2 - 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.
AB - 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.
KW - Ferroportin 1
KW - Heme oxygenase
KW - Hemojuvelin
KW - Transferrin receptor 1
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U2 - 10.1073/pnas.1215349109
DO - 10.1073/pnas.1215349109
M3 - Article
C2 - 23169664
AN - SCOPUS:84873628363
SN - 0027-8424
VL - 109
SP - 20590
EP - 20595
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -