{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:07:19Z","timestamp":1791295639607,"version":"4.1.0"},"reference-count":22,"publisher":"National Academy of Sciences","issue":"50","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,12,11]]},"abstract":"<jats:p>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, M\u00f6ssbauer 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.<\/jats:p>","DOI":"10.1073\/pnas.1215349109","type":"journal-article","created":{"date-parts":[[2012,11,20]],"date-time":"2012-11-20T22:10:06Z","timestamp":1353449406000},"page":"20590-20595","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":91,"title":["Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia"],"prefix":"10.1073","volume":"109","author":[{"given":"Megan","family":"Whitnall","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohan Suryo","family":"Rahmanto","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.-H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Saletta","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiu Chuen","family":"Lok","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Instituto de Ciencia de Materiales de Madrid\/Consejo Superior de Investigaciones Cient\u00edficas, Cantoblanco, 28049 Madrid, Spain;"},{"name":"School of Physics, University of Western Australia, Perth 6009, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"L\u00e1zaro","sequence":"additional","affiliation":[{"name":"Departamento de Ciencia y Tecnolog\u00eda de Materiales y Fluidos, Universidad de Zaragoza, 50018 Zaragoza, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Fleming","sequence":"additional","affiliation":[{"name":"School of Physics, University of Western Australia, Perth 6009, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim G.","family":"St. Pierre","sequence":"additional","affiliation":[{"name":"School of Physics, University of Western Australia, Perth 6009, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc R.","family":"Mikhael","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada H3T 1E2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prem","family":"Ponka","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada H3T 1E2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Des R.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Sydney, Sydney 2006, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,11,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-10-3856"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/84818"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg096"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906784106"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804261105"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01526.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912925107"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.028"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600041"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.1.178-185.2003"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200701049"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.8.3477.bloodjournal8783477"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(82)90043-X"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0892-0354(92)90011-E"},{"key":"e_1_3_3_15_2","first-page":"295","volume-title":"Biomineralization: Chemical and Biochemical Perspectives","author":"St Pierre TG","year":"1989","unstructured":"TG St Pierre, J Webb, S Mann, Ferritin and hemosiderin: Structural and magnetic studies of the iron core. 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