title: Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia.
abstract: BACKGROUND
  Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression.
  
  
  RESULTS
  We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide.
  
  
  CONCLUSIONS
  Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.
authors.affiliation: Inserm, U676, Hôpital Robert Debré, Bât. Ecran, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Paupe
authors.forename: Emmanuel P
authors.initials: EP
authors.lastname: Dassa
authors.forename: Sergio
authors.initials: S
authors.lastname: Goncalves
authors.forename: Françoise
authors.initials: F
authors.lastname: Auchère
authors.forename: Maria
authors.initials: M
authors.lastname: Lönn
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000378:metabolism; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D005621:Friedreich Ataxia / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000737:chemistry; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D007506:Iron-Sulfur Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D006861:Hydrogen Peroxide