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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5219-5227. Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2008-06-161919. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-06-161919v1 112/13/5219    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kakhlon, O. Articles by Cabantchik, Z. I. Search for Related Content PubMed PubMed Citation Articles by Kakhlon, O. Articles by Cabantchik, Z. I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 5, 2008 Accepted August 14, 2008 Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation Or Kakhlon*, Hila Manning, William Breuer, Naomi Melamed-Book, Chunye Lu, Gino Cortopassi, Arnold Munnich, and Z. Ioav Cabantchik Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel Department of Molecular Biosciences, University of California, Davis, CA, United States Medical Genetic Clinic and Research Unit INSERM 781, Hopital Necker-Enfants Malades and Universite Paris V Rene Descartes, Paris, France * Corresponding author; email: ork{at}cc.huji.ac.il. Various human disorders are associated with misdistribution of iron within or across cells. In Friedriech's ataxia (FRDA), a deficiency in the mitochondrial iron-chaperone frataxin results in defective utilization of iron and its misdistribution between mitochondria and cytosol. We assessed the possibility of functionally correcting the cellular properties affected by frataxin deficiency with a siderophore capable of relocating iron and facilitating its metabolic utilization. Adding the chelator deferiprone at clinical concentrations to inducibly frataxin-deficient HEK-293 cells resulted in chelation of mitochondrial labile iron involved in oxidative stress and in reactivation of iron-depleted aconitase. These led to: a. restoration of impaired mitochondrial membrane and redox potentials, b. increased ATP production and oxygen consumption and c. attenuation of mitochondrial DNA damage and reversal of hypersensitivity to staurosporine-induced apoptosis. Permeant chelators of higher affinity than deferiprone were not as efficient in restoring affected functions. Thus while iron chelation might protect cells from iron toxicity, rendering the chelated iron bioavailable might underlie deferiprone's capacity to restore cell functions affected by frataxin-deficiency, as also observed in FRDA patients. The siderophore-like properties of deferiprone provide a rational basis for treating diseases of iron misdistribution, such as FRDA, anemia of chronic disease and X-Linked Sideroblastic Anemia with Ataxia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Siddiq, L. R. Aminova, C. M. Troy, K. Suh, Z. Messer, G. L. Semenza, and R. R. Ratan Selective Inhibition of Hypoxia-Inducible Factor (HIF) Prolyl-Hydroxylase 1 Mediates Neuroprotection against Normoxic Oxidative Death via HIF- and CREB-Independent Pathways J. Neurosci., July 8, 2009; 29(27): 8828 - 8838. [Abstract] [Full Text] [PDF]

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