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 A Cortopassi, Arnold Munnich, Z. Ioav Cabantchik

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


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 de-feriprone 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 triphos-phate 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.

Original languageEnglish (US)
Pages (from-to)5219-5227
Number of pages9
Issue number13
StatePublished - Dec 15 2008

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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