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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1690-1699.
Prepublished online as a Blood First Edition Paper on November 1, 2007; DOI 10.1182/blood-2007-07-102335.
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Submitted July 19, 2007
Accepted October 25, 2007
Redistribution of accumulated cell iron. A modality of chelation with therapeutic implications
Yang-Sung Sohn, William Breuer, Arnold Munnich, and Z Ioav Cabantchik*
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
Clinical Research Unit, Med. Genetic Clinic & Research Unit, Hopital Necker-Enfants Malades and Universite Paris V Rene Descartes, Paris, France
* Corresponding author; email: ioav{at}cc.huji.ac.il.
Various pathologies are characterized by the accumulation of toxic iron in cell compartments. In anemia of chronic disease, iron is withheld by macrophages, leaving extracellular fluids iron-depleted. In Friedreich's ataxia, iron levels rise in the mitochondria of excitable cells, while decreasing in the cytosol. We explored the possibility of employing deferiprone, a membrane-permeant iron chelator in clinical use, to capture labile iron accumulated in specific organelles of cardiomyocytes and macrophages and convey it to other locations for physiological reutilization. Deferiprone's capacity to shuttle iron between cellular organelles was assessed with organelle-targeted fluorescent iron-sensors in conjunction with time-lapse fluorescence microscopy imaging. Deferiprone facilitated transfer of iron from extracellular medium into nuclei and mitochondria, from nuclei to mitochondria, from endosomes to nuclei and from intracellular compartments to extracellular apotransferrin. Furthermore, it mobilized iron from iron-loaded cells and donated it to pre-erythroid cells for hemoglobin synthesis, both in the presence and absence of transferrin. These unique properties of deferiprone underlie mechanistically its capacity to alleviate iron accumulation in dentate nuclei of Friedreich's ataxia patients and to donate tissue-chelated iron to plasma transferrin in thalassemia intermedia patients. Thus, deferiprone's shuttling properties could be exploited clinically for treating diseases involving regional iron-accumulation
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