Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation

Blood. 2008 Dec 15;112(13):5219-27. doi: 10.1182/blood-2008-06-161919. Epub 2008 Sep 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Cell Line
  • DNA Damage / drug effects
  • DNA, Mitochondrial
  • Deferiprone
  • Friedreich Ataxia
  • Humans
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology*
  • Iron-Binding Proteins / physiology*
  • Mitochondria / chemistry
  • Mitochondria / drug effects
  • Oxygen Consumption / drug effects
  • Pyridones / pharmacology*


  • DNA, Mitochondrial
  • Iron Chelating Agents
  • Iron-Binding Proteins
  • Pyridones
  • frataxin
  • Deferiprone
  • Adenosine Triphosphate
  • Iron