BackgroundFriedreich 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.Methodology/Principal FindingsWe 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/SignificanceThus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.

Background:The enzyme myeloperoxidase produces chlorine bleach at sites of inflammation. Results: 2-Thioxanthines are potent mechanism-based inactivators of myeloperoxidase. Conclusion: 2-Thioxanthines block production of chlorine bleach during inflammation. Significance: Mechanism-based inactivators of myeloperoxidase should limit oxidative stress at sites of inflammation.

Gex1 is a glutathione exchanger mostly found at the vacuolar membrane. The expression of Gex1 and Gex2 is induced under conditions of iron depletion, and Gex1 is regulated principally by the iron transcription factor Aft2. Loss of or high Gex1/2 activity modulates PKA and MAPK signaling events.

Background: Myeloperoxidase causes oxidative damage in many inflammatory diseases. Results: New substituted aromatic hydroxamates are identified as potent, selective, and reversible inhibitors of MPO. Conclusion: Binding affinities of hydroxamates to the heme pocket determine the potency of inhibition. Significance: Compounds that bind tightly to the active site of myeloperoxidase have potential as therapeutically useful inhibitors of oxidative stress.

Friedreich's ataxia is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulphur cluster defects and high sensitivity to oxidative stress. Glutathione is a major protective agent against oxidative damage and glutathione-related systems participate in maintaining the cellular thiol/disulfide status and the reduced environment of the cell. Here, we present the first detailed biochemical study of the glutathione-dependent redox status of wild-type and frataxin-deficient cells in a yeast model of the disease. There were five times less total glutathione (GSH+GSSG) in frataxin-deficient cells, imbalanced GSH/GSSG pools and higher glutathione peroxidase activity. The pentose phosphate pathway was stimulated in frataxin-deficient cells, glucose-6-phosphate dehydrogenase activity was three times higher than in wild-type cells and this was coupled to a defect in the NADPH/NADP(+) pool. Moreover, analysis of gene expression confirms the adaptative response of mutant cells to stress conditions and we bring evidence for a strong relation between the glutathione-dependent redox status of the cells and iron homeostasis. Dynamic studies show that intracellular glutathione levels reflect an adaptation of cells to iron stress conditions, and allow to distinguish constitutive stress observed in frataxin-deficient cells from the acute response of wild-type cells. In conclusion, our findings provide evidence for an impairment of glutathione homeostasis in a yeast model of Friedreich's ataxia and identify glutathione as a valuable indicator of the redox status of frataxin-deficient cells.

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For three decades, oxidative stress and the role of reactive oxygen species in biology have been extensively studied. Recently, a new interest in these areas has emerged with the discovery of superoxide reductases, a family of familiar bacterial metalloenzymes whose heretofore unknown function has now been apparently revealed. In a series of experiments utilizing genetic, molecular biological, and biochemical methods, these enzymes have been shown to be physiologically competent at removing superoxide. The role of these enzymes and their biological relationship to the well-known superoxide dismutases is discussed.

Superoxide reductase (SOR) is a metalloprotein containing a non-heme iron centre, responsible for the scavenging of superoxide radicals in the cell. The crystal structure of Treponema pallidum (Tp) SOR was determined using soft X-rays and synchrotron radiation. Crystals of the oxidized form were obtained using poly(ethylene glycol) and MgCl 2 and diffracted beyond 1.55 Å resolution. The overall architecture is very similar to that of other known SORs but TpSOR contains an N-terminal domain in which the desulforedoxin-type Fe centre, found in other SORs, is absent. This domain conserves the b-barrel topology with an overall arrangement very similar to that of other SOR proteins where the centre is present. The absence of the iron ion and its ligands, however, causes a decrease in the cohesion of the domain and some disorder is observed, particularly in the region where the metal would be harboured. The C-terminal domain exhibits the characteristic immunoglobulin-like fold and harbours the Fe(His) 4 (Cys) active site. The five ligands of the iron centre are well conserved despite some disorder observed for one of the four molecules in the asymmetric unit. The participation of a glutamate as the sixth ligand of some of the iron centres in Pyrococcus furiosus SOR was not observed in TpSOR. A possible explanation is that either X-ray photoreduction occurred or there was a mixture of redox states at the start of data collection. In agreement with earlier proposals, details in the TpSOR structure also suggest that Lys49 might be involved in attraction of superoxide to the active site.