title: Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Or
authors.initials: O
authors.lastname: Kakhlon
authors.forename: Hila
authors.initials: H
authors.lastname: Manning
authors.forename: William
authors.initials: W
authors.lastname: Breuer
authors.forename: Naomi
authors.initials: N
authors.lastname: Melamed-Book
authors.forename: Chunye
authors.initials: C
authors.lastname: Lu
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Z Ioav
authors.initials: ZI
authors.lastname: Cabantchik
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D004272:DNA, Mitochondrial; D000077543:Deferiprone; D005621:Friedreich Ataxia; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D033862:Iron-Binding Proteins / Q000502:physiology*; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D000096923:Frataxin
chemical_list: D000255:Adenosine Triphosphate; D004272:DNA, Mitochondrial; D000077543:Deferiprone; D007501:Iron; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D011728:Pyridones; D000096923:Frataxin