MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation
There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle crea...
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description | There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant. |
doi_str_mv | 10.1073/pnas.0804261105 |
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The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0804261105</identifier><identifier>PMID: 18621680</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Biological Transport ; Body weight ; Cardiomegaly - etiology ; Cardiomegaly - metabolism ; Cardiomyopathies ; Cardiovascular disease ; Chelation ; Cytosol ; Disease Models, Animal ; Ferritins ; Ferritins - analysis ; Ferritins - metabolism ; Frataxin ; Friedreich ataxia ; Friedreich Ataxia - complications ; Friedreich Ataxia - etiology ; Friedreich Ataxia - metabolism ; Gene expression ; Iron ; Iron - metabolism ; Iron Chelating Agents - pharmacology ; Iron-Binding Proteins - genetics ; Iron-Binding Proteins - metabolism ; Messenger RNA ; Mice ; Mice, Knockout ; Mitochondria ; Mitochondria - metabolism ; Mutants ; Mutation ; Pathology ; Receptors, Cell Surface - metabolism ; Rodents ; Vehicles</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-07, Vol.105 (28), p.9757-9762</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jul 15, 2008</rights><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-b57cd84f714d7b6f2e745aa9c8a0fcc13050962b4b6d3ba234b5e16cda02af4f3</citedby><cites>FETCH-LOGICAL-c587t-b57cd84f714d7b6f2e745aa9c8a0fcc13050962b4b6d3ba234b5e16cda02af4f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/28.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25463046$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25463046$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18621680$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Whitnall, Megan</creatorcontrib><creatorcontrib>Rahmanto, Yohan Suryo</creatorcontrib><creatorcontrib>Sutak, Robert</creatorcontrib><creatorcontrib>Xu, Xiangcong</creatorcontrib><creatorcontrib>Becker, Erika M</creatorcontrib><creatorcontrib>Mikhael, Marc R</creatorcontrib><creatorcontrib>Ponka, Prem</creatorcontrib><creatorcontrib>Richardson, Des R</creatorcontrib><title>MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Biological Transport</subject><subject>Body weight</subject><subject>Cardiomegaly - etiology</subject><subject>Cardiomegaly - metabolism</subject><subject>Cardiomyopathies</subject><subject>Cardiovascular disease</subject><subject>Chelation</subject><subject>Cytosol</subject><subject>Disease Models, Animal</subject><subject>Ferritins</subject><subject>Ferritins - analysis</subject><subject>Ferritins - metabolism</subject><subject>Frataxin</subject><subject>Friedreich ataxia</subject><subject>Friedreich Ataxia - complications</subject><subject>Friedreich Ataxia - etiology</subject><subject>Friedreich Ataxia - metabolism</subject><subject>Gene expression</subject><subject>Iron</subject><subject>Iron - metabolism</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Iron-Binding Proteins - genetics</subject><subject>Iron-Binding Proteins - metabolism</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Pathology</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Rodents</subject><subject>Vehicles</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kkGP0zAQhSMEYsvCmRNgcYFLdseOnTgckFYVC4hFHGDP1sRxGldpHGwHbf8Cvxp3W7Vw4WDZ0nzvzYyes-w5hQsKVXE5jRguQAJnJaUgHmQLCjXNS17Dw2wBwKpccsbPsichrAGgFhIeZ2dUloyWEhbZ76_LL2Tj5mBIb9DH9G7NQFxHrr01rTdW928CwYh3Ft-RqyEaj9G6MRA7EuvdmHuzmgeMpiWTd9HYVMKxJRp9a1GTfjsZH72b-i1Bb8hgN3YHN9t7OdG9Ge4dn2aPOhyCeXa4z7Pb6w8_lp_ym28fPy-vbnItZBXzRlS6lbyrKG-rpuyYqbhArLVE6LSmBQioS9bwpmyLBlnBG2FoqVsEhh3vivPs_d53mpuNabUZo8dBTd5u0G-VQ6v-rYy2Vyv3SzGeOtEiGbw-GHj3czYhqrWb_ZhmVgwokxJEnaDLPaS9C8Gb7tiAgtplp3bZqVN2SfHy77lO_CGsBLw9ADvlyU4oJlVdiUp185ACuosJffV_NBEv9sQ6ROePCBO8LCCdo0OHTuHK26Buv6f1ivSJaMk5Lf4AFinD3Q</recordid><startdate>20080715</startdate><enddate>20080715</enddate><creator>Whitnall, Megan</creator><creator>Rahmanto, Yohan Suryo</creator><creator>Sutak, Robert</creator><creator>Xu, Xiangcong</creator><creator>Becker, Erika M</creator><creator>Mikhael, Marc R</creator><creator>Ponka, Prem</creator><creator>Richardson, Des R</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20080715</creationdate><title>MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation</title><author>Whitnall, Megan ; 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The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18621680</pmid><doi>10.1073/pnas.0804261105</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biological Sciences Biological Transport Body weight Cardiomegaly - etiology Cardiomegaly - metabolism Cardiomyopathies Cardiovascular disease Chelation Cytosol Disease Models, Animal Ferritins Ferritins - analysis Ferritins - metabolism Frataxin Friedreich ataxia Friedreich Ataxia - complications Friedreich Ataxia - etiology Friedreich Ataxia - metabolism Gene expression Iron Iron - metabolism Iron Chelating Agents - pharmacology Iron-Binding Proteins - genetics Iron-Binding Proteins - metabolism Messenger RNA Mice Mice, Knockout Mitochondria Mitochondria - metabolism Mutants Mutation Pathology Receptors, Cell Surface - metabolism Rodents Vehicles |
title | MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation |
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