Increasing evidence suggests that iron-mediated oxidative stress might underlie the development of neurodegeneration in Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by decreased expression of frataxin, a protein implicated in iron metabolism. In this study, we demonstrate that, in fibroblasts of patients with FRDA, the cellular redox equilibrium is shifted toward more protein-bound glutathione. Furthermore, we found that actin is glutathionylated, probably as a result of the accumulation of reactive oxygen species, generated by iron overload in the disease. Indeed, high-pressure liquid chromatography analysis of control fibroblasts in vivo treated with FeSO4 showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation. Actin glutathionylation contributes to impaired microfilament organization in FRDA fibroblasts. Rhodamine phalloidin staining revealed a disarray of actin filaments and a reduced signal of F-actin fluorescence. The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. When we treated FRDA fibroblasts with reduced glutathione, we obtained a complete rescue of cytoskeletal abnormalities and cell viability. Thus, we conclude that oxidative stress may induce actin glutathionylation and impairment of cytoskeletal functions in FRDA fibroblasts. Increasing evidence suggests that iron-mediated oxidative stress might underlie the development of neurodegeneration in Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by decreased expression of frataxin, a protein implicated in iron metabolism. In this study, we demonstrate that, in fibroblasts of patients with FRDA, the cellular redox equilibrium is shifted toward more protein-bound glutathione. Furthermore, we found that actin is glutathionylated, probably as a result of the accumulation of reactive oxygen species, generated by iron overload in the disease. Indeed, high-pressure liquid chromatography analysis of control fibroblasts in vivo treated with FeSO4 showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation. Actin glutathionylation contributes to impaired microfilament organization in FRDA fibroblasts. Rhodamine phalloidin staining revealed a disarray of actin filaments and a reduced signal of F-actin fluorescence. The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. When we treated FRDA fibroblasts with reduced glutathione, we obtained a complete rescue of cytoskeletal abnormalities and cell viability. Thus, we conclude that oxidative stress may induce actin glutathionylation and impairment of cytoskeletal functions in FRDA fibroblasts. Oxidative stress has been proposed to underlie neurodegeneration in Friedreich's ataxia (FRDA), 1The abbreviations used are: FRDA, Friedreich's ataxia; HPLC, high-pressure liquid chromatography; EE-GSH, ethyl ester-reduced glutathione.1The abbreviations used are: FRDA, Friedreich's ataxia; HPLC, high-pressure liquid chromatography; EE-GSH, ethyl ester-reduced glutathione. the most common of the hereditary ataxias, caused by severely reduced levels of frataxin, a protein implicated in iron metabolism. FRDA is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence of diabetes. Most patients (95%) are homozygous for the hyperexpansion of a GAA repeat sequence in the first intron of the frataxin gene; a few are heterozygous for a GAA expansion and a point mutation (1Puccio H. Koenig M. Hum. Mol. Genet. 2000; 9: 887-892Crossref PubMed Scopus (123) Google Scholar, 2Patel P.I. Isaya G. Am. J. Hum. Genet. 2001; 69: 15-24Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 3Pandolfo M. Arch. Neurol. 1999; 56: 1201-1208Crossref PubMed Scopus (101) Google Scholar). Data from yeast suggest that frataxin deficiency results in iron accumulation within mitochondria and increased sensitivity to oxidative stress (4Knight S.A.B. Kim R. Pain D. Dancis A. Am. J. Hum. Genet. 1999; 64: 365-371Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 5Radisky D.C. Babcock M.C. Kaplan J. J. Biol. Chem. 1999; 274: 4497-4499Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar). Mouse models for FRDA exhibit cardiomyopathy, sensory nerve defects, and Fe-S enzyme deficiency followed by intramitochondrial iron deposits (6Puccio H. Simon D. Cossee M. Crique-Filipe P. Tiziano F. Melki J. Hindelang C. Matyas R. Rustin P. Koenig M. Nat. Genet. 2001; 27: 181-186Crossref PubMed Scopus (598) Google Scholar). Patients with FRDA have iron deposits in the heart, increased mitochondrial iron in fibroblasts, and greater sensitivity to oxidative stress by pro-oxidants such as FeCl3 and hydrogen peroxide (3Pandolfo M. Arch. Neurol. 1999; 56: 1201-1208Crossref PubMed Scopus (101) Google Scholar, 7Delatycki M.B. Camakaris J. Brooks H. Evans-Whipp T. Thorburn D.R. Williamson R. Forrest S.M. Ann. Neurol. 1999; 45: 673-675Crossref PubMed Scopus (155) Google Scholar, 8Wong A. Yang J. Cavadini P. Gellera C. Lonnerdal B. Taroni F. Cortopassi G. Hum. Mol. Genet. 1999; 8: 425-430Crossref PubMed Scopus (324) Google Scholar). Furthermore, a defective mitochondrial respiratory chain has been found in FRDA tissues, in association with iron accumulation and moderate decreases in mtDNA levels (9Bradley J.L. Blake J.C. Chamberlain S. Thomas P.K. Cooper J.M. Schapira A.H.V. Hum. Mol. Genet. 2000; 9: 275-282Crossref PubMed Scopus (303) Google Scholar, 10Vorgerd M. Schols L. Hardt C. Ristow M. Epplen J.T. Zange J. Neuromuscular Disorders. 2000; 10: 430-435Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Iron is a crucial reagent in the Fenton reaction, as it can react with mitochondrially generated superoxide anion ( O2˙- ) to produce the toxic hydroxyl radical (OH.) , and iron-mediated oxidative stress has been hypothesized to underlie the pathophysiology of the disease. Increased levels of oxidative stress markers such as plasma malondialdehyde and urine 8-hydroxy-2-deoxyguanosine have been found in patients with FRDA, and improvement of cardiac and skeletal muscle bioenergetics has been observed after antioxidant treatment (11Edmond M. Lepage G. Vanasse M. Pandolfo M. Neurology. 2000; 55: 1752-1753Crossref PubMed Scopus (159) Google Scholar, 12Schulz J.B. Dehmer T. Schols L. Mende H. Hardt C. Vorgerd M. Burk K. Matson W. Dichgans J. Beal M.F. Bogdanov M.B. Neurology. 2000; 55: 1719-1721Crossref PubMed Scopus (284) Google Scholar, 13Lodi R. Hart P.E. Rajagopalan B. Taylor D.J. Phil D. Crilley J.G. Bradley J.L. Blamire A.M. Manners D. Styles P. Schapira A.H. Cooper J.M. Ann. Neurol. 2001; 49: 590-596Crossref PubMed Scopus (194) Google Scholar, 14Lerman-Sagie T. Rustin P. Lev D. Yanoov M. Leshinsky-Silver E. Sagie A. Ben-Gal T. Munnich A. J. Inherit. Metab. Dis. 2001; 24: 28-34Crossref PubMed Scopus (49) Google Scholar, 15Housse A.O. Aggoun Y. Bonnet D. Sidi D. Munnich A. Rotig A. Rustin P. Heart (Lond.). 2002; 87: 346-349Google Scholar). Moreover, we found an impairment in vivo of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and decreased levels of free glutathione in the blood of patients with FRDA (16Tozzi G. Nuccetelli M. Lo Bello M. Bernardini S. Bellincampi L. Ballerini S. Gaeta L.M. Casali C. Pastore A. Federici G. Bertini E. Piemonte F. Arch. Dis. Child. 2002; 86: 376-380Crossref PubMed Scopus (50) Google Scholar, 17Piemonte F. Pastore A. Tozzi G. Tagliacozzi D. Santorelli F.M. Carrozzo R. Casali C. Damiano M. Federici G. Bertini E. Eur. J. Clin. Investig. 2001; 31: 1007-1011Crossref PubMed Scopus (152) Google Scholar). In cells, exposure to acute oxidative stress triggers a sequence of events characterized by depletion of antioxidant defenses and oxidative modification of proteins, lipids, and nucleic acids. Protein thiols are particularly susceptible to oxidation and may represent important targets in redox signaling. Recently, protein glutathionylation has gained attention as a possible means of protein function redox regulation. One proposed mechanism leading to protein S-glutathionylation in vivo is the thiol/disulfide exchange mechanism (18Gilbert H.F. Methods Enzymol. 1995; 251: 8-28Crossref PubMed Scopus (494) Google Scholar), which occurs when an oxidative insult changes the GSH/GSSG ratio and induces GSSG to bind to protein thiols. Several important enzymes, including phosphofructokinase (19Gilbert H.F. J. Biol. Chem. 1982; 257: 12086-12091Abstract Full Text PDF PubMed Google Scholar), glycogen synthase (20Ernest M.J. Kim K.H. J. Biol. Chem. 1974; 249: 5011-5018Abstract Full Text PDF PubMed Google Scholar), fructose-1,6-diphosphatase (21Nakashima K. Horecker B.L. Pontremoli S. Arch. Biochem. Biophys. 1970; 141: 579-587Crossref PubMed Scopus (23) Google Scholar), 3-hydroxy-3-methylglutaryl-CoA reductase (22Cappel R.E. Gilbert H.F. J. Biol. Chem. 1989; 264: 9180-9187Abstract Full Text PDF PubMed Google Scholar), glyceraldehyde-3-phosphate dehydrogenase (23Ravichandran V. Seres T. Moriguchi T. Thomas J.A. Johnston R.B. J. Biol. Chem. 1994; 269: 25010-25015Abstract Full Text PDF PubMed Google Scholar), protein kinase C (24Ward N.E. Pierce D.S. Chung S.E. Gravitt K.R. O'Brian C.A. J. Biol. Chem. 1998; 273: 12558-12566Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar), and guanylate cyclase (25Brandwein H.J. Lewicki J.A. Murad F. J. Biol. Chem. 1981; 256: 2958-2962Abstract Full Text PDF PubMed Google Scholar), and glucocorticoid receptors (26Silva C.M. Cidiowski J.A. J. Biol. Chem. 1989; 264: 6638-6647Abstract Full Text PDF PubMed Google Scholar) are potentially influenced by the formation of protein adducts with glutathione. Also transcription factors such as c-Jun appear to be redox-regulated by mechanisms that include protein S-thiolation (27Klatt P. Molina E.S. Lacoba M.C. Padilla C.A. Mrtinez-Glaisteo E. Barcena J.A. Lamas S. FASEB J. 1999; 13: 1481-1490Crossref PubMed Scopus (250) Google Scholar, 28Klatt P. Molina E.P. Lamas S. J. Biol. Chem. 1999; 274: 15857-15864Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), and ubiquitin-activating enzymes become S-glutathionylated, with a concomitant decrease in the ubiquitinylation pathway, when cells are exposed to oxidants (29Jahnegen-Hodge J. Obin M.S. Gong X. Shang F. Novell T.R. Gong J. Abasi H. Blumberg J. Taylor A. J. Biol. Chem. 1997; 272: 28218-28226Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar). A reversible glutathionylation was found to regulate actin polymerization in human epidermal carcinoma cells (30Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Cock B. J. Biol. Chem. 2001; 276: 47763-47766Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar), and S-glutathionylation, followed by inactivation, was reported for creatine kinase, a crucial source of ATP in myocytes, during oxidative stress (31Reddy S. Jones A.D. Cross C.E. Wong P.S.Y. Van der Vliet A. Biochem. J. 2000; 347: 821-827Crossref PubMed Scopus (109) Google Scholar). Furthermore, we recently found an increase in glutathionyl-hemoglobin in the blood of patients with FRDA, accompanied by a significant decrease in free glutathione (17Piemonte F. Pastore A. Tozzi G. Tagliacozzi D. Santorelli F.M. Carrozzo R. Casali C. Damiano M. Federici G. Bertini E. Eur. J. Clin. Investig. 2001; 31: 1007-1011Crossref PubMed Scopus (152) Google Scholar). Free glutathione concentration, mainly represented by its reduced form, is a limiting factor in many detoxifying processes by protecting protein thiol groups from oxidation, as a free radical as a for a of important enzymes such as glutathione peroxidase and glutathione Free 1999; 31: PubMed Scopus Google Scholar). of increased stress such as and in glutathione is a factor in of mitochondrial function and cell as as transcription factor and J.C. C. A. M. M. E. A. Am. J. 1997; 273: PubMed Google Scholar). The glutathione, oxidative and neurodegeneration was recently by J.B. J. J. Dichgans J. Eur. J. Biochem. 2000; PubMed Scopus Google Scholar), and an important for glutathione has been proposed for the of a decrease in GSH in the was observed in of the E. K. P. PubMed Scopus Google Scholar). the of FRDA is is that the of reactive the Fenton reaction, free within the leading to oxidative Thus, in of evidence a crucial for glutathione in the of cellular in to oxidative and stress P. Lamas S. Eur. J. Biochem. 2000; PubMed Scopus Google Scholar, M. H. M. S. M. V. M. F. E. A. J. E. P. S. A. 2002; PubMed Scopus Google Scholar), we the redox of glutathione in fibroblasts of patients with FRDA and a protein that glutathionylation in this we obtained from patients with FRDA and and protein-bound glutathione by high-pressure liquid chromatography In we the protein by Western a was obtained from and from Rhodamine phalloidin was from Protein was from The protein was obtained from for cell from from from FRDA patients and and in with and in to The in and was and used with the cells in of for and to of of cells for in of of and the GSH in the was The protein was in of and protein-bound GSH was glutathione cells for in of GSH was in GSH levels by GSSG from free GSH Protein by the protein and chromatography as reported A. Piemonte F. M. Lo A. Gaeta L.M. Tozzi G. Federici G. Clin. Chem. 2001; PubMed Scopus Google Scholar). of by Western of to and the to a The was with in and for and with of Actin by in of and with of for and of the of protein to the and for a The was by for and with a the was in of for a for Western blot and revealed with of of glutathionylation was by with a Data and to the of protein the and to glutathione in fibroblasts. of Rhodamine with in for with and with a with and a with in for and with for treatment with cells with for with for with and and with the with a in of and Actin and and of patients with FRDA for with GSH and in the and of a by Western as to the of actin glutathionylation. FRDA cells to and by staining with phalloidin and was a that in cells by the of a and the results the in of Actin of FeSO4 treatment was by control fibroblasts in vivo with FeSO4 for and GSH levels by analysis as Western blot analysis was cells treated with FeSO4 for and in of fibroblasts treated in vivo with FeSO4 for and to by staining with phalloidin the glutathione in fibroblasts of FRDA patients and the GSH/GSSG and GSH and protein-bound/free GSH The GSH/GSSG ratio was in and decreased to in FRDA fibroblasts The GSH ratio was in control cells and increased to in FRDA cells The protein-bound/free GSH ratio was in control fibroblasts and increased to in FRDA patients results that FRDA fibroblasts oxidative with the cellular redox equilibrium shifted toward more protein-bound glutathione with to fibroblasts of was used to the glutathionylation of FRDA fibroblasts Western blot analysis of fibroblasts obtained from patients revealed a which was by the we the with and with in we obtained a to The of glutathionylation was increased by in FRDA patients with to of protein by staining of an the increase in actin glutathionylation in FRDA fibroblasts is to changes in the cytoskeletal we fibroblasts with the actin The revealed a significant of F-actin in FRDA patients with of the signal with FRDA fibroblasts to be with to fibroblasts of suggest that glutathionylation of actin to a disarray of actin size and abnormalities in FRDA fibroblasts. is an in vivo of glutathionylation in FRDA fibroblasts, we treated FRDA cells with GSH and for the results from a decrease in the protein-bound/free GSH ratio in FRDA fibroblasts and a in FRDA fibroblasts with analysis of GSH and GSSG levels revealed in GSH/GSSG to GSH treatment and to treatment with to FRDA cells to in Furthermore, Western blot analysis showed a decrease in in cells and a decrease in cells with FRDA fibroblasts GSH is to the cells, we in vivo by FRDA fibroblasts with an of that the obtained by GSH EE-GSH, which is was by the The of FRDA fibroblasts after of in vivo GSH treatment showed an increase in the phalloidin signal of F-actin and a rescue of cell size and analysis the cell showed a increase in the signal in FRDA cells with to cells to that in to is an in vivo association iron which the of FRDA, and actin we treated control fibroblasts with FeSO4 for and analysis showed and in the protein-bound/free GSH ratio, with Western blot analysis of fibroblasts with FeSO4 for and showed and in with cells Moreover, to FeSO4 induces changes of FRDA, we treated in vivo control cells with FeSO4 for significant changes in FRDA fibroblasts of control fibroblasts after in vivo FeSO4 cells treated in vivo with FeSO4 for and actin was by phalloidin The the of FRDA that frataxin is in the of mitochondrial iron and that impaired intramitochondrial iron results in iron overload and oxidative stress (1Puccio H. Koenig M. Hum. Mol. Genet. 2000; 9: 887-892Crossref PubMed Scopus (123) Google Scholar, 2Patel P.I. Isaya G. Am. J. Hum. Genet. 2001; 69: 15-24Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Iron deposits are observed in of FRDA patients and that iron in the (9Bradley J.L. Blake J.C. Chamberlain S. Thomas P.K. Cooper J.M. Schapira A.H.V. Hum. Mol. Genet. 2000; 9: 275-282Crossref PubMed Scopus (303) Google Scholar, J.B. D. M. B. R. of Scholar, D. P. M. Ann. Neurol. 1999; PubMed Scopus Google Scholar). In we reported a significant increase in glutathionyl-hemoglobin in the blood of patients with FRDA, with an the superoxide dismutase and glutathione peroxidase antioxidant enzyme the of a oxidative stress in the (16Tozzi G. Nuccetelli M. Lo Bello M. Bernardini S. Bellincampi L. Ballerini S. Gaeta L.M. Casali C. Pastore A. Federici G. Bertini E. Piemonte F. Arch. Dis. Child. 2002; 86: 376-380Crossref PubMed Scopus (50) Google Scholar, 17Piemonte F. Pastore A. Tozzi G. Tagliacozzi D. Santorelli F.M. Carrozzo R. Casali C. Damiano M. Federici G. Bertini E. Eur. J. Clin. Investig. 2001; 31: 1007-1011Crossref PubMed Scopus (152) Google Scholar). in of in the of FRDA, has the analysis of glutathione in fibroblasts of FRDA Furthermore, as the and reduced glutathione redox the of proteins, we the protein in FRDA fibroblasts. for the first that fibroblasts of patients with FRDA oxidative with a significant decrease in the GSH/GSSG In the cellular redox equilibrium is shifted toward more protein-bound glutathione, with significant in GSH and protein-bound/free GSH Furthermore, we used to protein glutathionylation in fibroblasts, and we found that are in FRDA, with a increase in FRDA Protein glutathionylation occurs in fibroblasts, to a The that are has been observed by M. H. M. S. M. V. M. F. E. A. J. E. P. S. A. 2002; PubMed Scopus Google Scholar) in and may a for glutathionylation in protein In for of of are as with R. C. H. Biochem. PubMed Scopus Google Scholar). can glutathionylation oxidative stress P. Lamas S. Eur. J. Biochem. 2000; PubMed Scopus Google Scholar, Biochem. Biophys. 1998; PubMed Scopus Google Scholar, P. M.J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). important such as in the of in the of and the and dehydrogenase is the protein in cells exposed to hydrogen peroxide and in during the oxidative (23Ravichandran V. Seres T. Moriguchi T. Thomas J.A. Johnston R.B. J. Biol. Chem. 1994; 269: 25010-25015Abstract Full Text PDF PubMed Google Scholar, P. T. Eur. J. Biochem. 1994; PubMed Scopus Google Scholar). kinase and glycogen are targets for S-glutathionylation in and cardiac during oxidative glutathione superoxide and become in cellular models of oxidative proteins, including 3-hydroxy-3-methylglutaryl-CoA human and have been reported as targets in for S-glutathionylation P. Lamas S. Eur. J. Biochem. 2000; PubMed Scopus Google Scholar). c-Jun to be redox-regulated by glutathionylation (27Klatt P. Molina E.S. Lacoba M.C. Padilla C.A. Mrtinez-Glaisteo E. Barcena J.A. Lamas S. FASEB J. 1999; 13: 1481-1490Crossref PubMed Scopus (250) Google Scholar, 28Klatt P. Molina E.P. Lamas S. J. Biol. Chem. 1999; 274: 15857-15864Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), and is by S-glutathionylation during oxidative stress T. J.T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In was to mitochondrial by glutathionylation of respiratory chain enzymes G. R. S. A. 1997; PubMed Scopus Google Scholar). glutathionylation of by superoxide anion has been in a that S-glutathionylation of the of cells and protein function M.B. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of the found to be to the of cytoskeletal proteins, which are particularly in The organization of the of exposed the modification of groups by glutathionylation be relevant to by protecting oxidation polymerization K. R.B. K. Am. J. 1994; Google Scholar, A. D. P. R. R. J. 2000; PubMed Scopus Google Scholar, D. R. R. A. Free Biol. PubMed Scopus Google Scholar). In this study, we have that the glutathionylation of actin caused an impairment of in FRDA fibroblasts, as showed the actin The revealed a and reduced signal of probably to of actin The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. the of FRDA fibroblasts was that of control cells as by analysis Actin is of the cytoskeletal proteins, an important in the and of the polymerization is a implicated in cytoskeletal (30Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Cock B. J. Biol. Chem. 2001; 276: 47763-47766Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar) the epidermal to in vivo of actin with an increase in protein glutathionylation as a relevant mechanism in actin by the for actin polymerization was that for actin polymerization obtained in the of GSSG (30Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Cock B. J. Biol. Chem. 2001; 276: 47763-47766Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). Recently, D. R. R. A. Free Biol. PubMed Scopus Google Scholar) in that actin has a decreased to with with impaired microfilament organization by glutathione has been reported in the of glutathione of actin in filaments with a K. Johnston R.B. Thomas J.A. Arch. Biochem. Biophys. 1994; PubMed Scopus Google Scholar, A. D. A. A. C. 1999; PubMed Scopus Google Scholar). The glutathionylation of actin has been observed in cells of oxidative cells treated with and and human K. R.B. K. Am. J. 1994; Google Scholar, C. G. H. H. Biophys. PubMed Scopus Google Scholar). treatment is for actin glutathionylation in human epidermal carcinoma cells, it actin polymerization (30Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Cock B. J. Biol. Chem. 2001; 276: 47763-47766Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). A of actin has been reported in such as in a of degeneration to be to defective of for F. 1995; PubMed Scopus Google Scholar). Actin oxidation was in of patients with that oxidative may to the degeneration of neurons in the 2001; PubMed Scopus Google Scholar). is a reversible mechanism (30Wang J. Boja E.S. Tan W. Tekle E. Fales H.M. English S. Mieyal J.J. Cock B. J. Biol. Chem. 2001; 276: 47763-47766Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, D. R. R. A. Free Biol. PubMed Scopus Google Scholar). Indeed, when we fibroblasts with pro-oxidants in we found a increase in glutathionylation in the of GSSG and a increase with was in by GSH the in vivo of actin glutathionylation in FRDA, we treated fibroblasts with GSH for and the of glutathionylation and cell we found a decrease in protein glutathionylation in treated fibroblasts analysis by Western and a complete rescue of size and cell shape. cell in a significant of the signal in FRDA cells, to that in GSH cell is have GSH which to the of Free 1999; 31: PubMed Scopus Google Scholar). for of glutathione has been in the and in the J. 1998; Google Scholar, A. Federici G. Bertini E. Piemonte F. Clin. PubMed Scopus Google Scholar). to GSH is to the cells, we treated FRDA fibroblasts in vivo with an of and we found that the obtained by GSH to Thus, GSH to be by the cells, the of EE-GSH, which is is by the the of GSH to the cells to be by be to the mechanism the in vivo of glutathione in of the of with to the protein-bound GSH oxidative has been proposed to underlie the of iron overload and actin as by in vivo of control fibroblasts with analysis showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation in fibroblasts with suggest a for iron-mediated oxidative stress in the glutathionylation in we significant changes of FRDA fibroblasts after FeSO4 treatment of control Thus, the changes observed in FRDA cells probably an cellular to iron which in is by the of it to be protein glutathionylation. In we that iron to frataxin deficiency to oxidative stress in FRDA, actin glutathionylation and impairment of cytoskeletal mechanism may to the of neurodegeneration in the disease.
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