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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 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 Citation Map 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. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation Or Kakhlon1, Hila Manning1, William Breuer1, Naomi Melamed-Book1, Chunye Lu2, Gino Cortopassi2, Arnold Munnich3, and Z. Ioav Cabantchik1 1 Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel; 2 Department of Molecular Biosciences, University of California, Davis; and 3 Medical Genetic Clinic and Research Unit, Inserm 781, Hôpital Necker-Enfants Malades and Université Paris V René Descartes, Paris, France Various human disorders are associated with misdistribution of iron within or across cells. Friedreich ataxia (FRDA), a deficiency in the mitochondrial iron-chaperone frataxin, results in defective use 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 use. 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 (1) restoration of impaired mitochondrial membrane and redox potentials, (2) increased adenosine triphosphate production and oxygen consumption, and (3) 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, although iron chelation might protect cells from iron toxicity, rendering the chelated iron bioavailable might underlie the capacity of deferiprone 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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