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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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2008-07, Vol.105 (28), p.9757-9762
Hauptverfasser: Whitnall, Megan, Rahmanto, Yohan Suryo, Sutak, Robert, Xu, Xiangcong, Becker, Erika M, Mikhael, Marc R, Ponka, Prem, Richardson, Des R
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container_issue 28
container_start_page 9757
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 105
creator Whitnall, Megan
Rahmanto, Yohan Suryo
Sutak, Robert
Xu, Xiangcong
Becker, Erika M
Mikhael, Marc R
Ponka, Prem
Richardson, Des R
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. 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source MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry
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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