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Deficiency of the cystine-transporter gene, xCT, does not exacerbate the deleterious phenotypic consequences of SOD1 knockout in mice

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Abstract

Because glutathione scavenges reactive oxygen species (ROS) and also donates electrons to antioxidative systems, it may compensate for the oxidative stress caused by SOD1 deficiency. The cystine/glutamate transporter, which consists of two proteins, xCT and 4F2hc, has been designated system x −c . This transporter system plays a role in the maintenance of glutathione levels in mammalian cells. In the present study, we created SOD1 −/−; xCT −/− double-knockout mice by intercrossing xCT-knockout and SOD1-knockout animals. We determined if the double-knockout mice express the phenotypic characteristics unique to SOD1 −/− mice—increased oxidative stress and the production of autoantibodies against erythrocytes. We also compared the phenotype of the double-knockout mice with those of the single-knockout and wild-type mice. Although two major antioxidative systems were found to be defective in the SOD1 −/−; xCT −/− mice, relative to the SOD1 −/− mice, no functional deficits were observed. Based on these results, it appears that defects in system x −c do not exacerbate the phenotypic consequences of SOD1 deficiency in postnatal mice under ordinary breeding conditions.

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References

  1. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112. doi:10.1146/annurev.bi.64.070195.000525

    Article  PubMed  CAS  Google Scholar 

  2. Okado-Matsumoto A, Fridovich I (2001) Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria. J Biol Chem 276:38388–38393. doi:10.1074/jbc.M105395200

    Article  PubMed  CAS  Google Scholar 

  3. Valentine JS, Doucette PA, Potter SZ (2005) Copper–zinc superoxide dismutase and amyotrophic lateral sclerosis. Annu Rev Biochem 74:563–593. doi:10.1146/annurev.biochem.72.121801.161647

    Article  PubMed  CAS  Google Scholar 

  4. Li Y, Huang TT, Carlson EJ et al (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11:376–381. doi:10.1038/ng1295-376

    Article  PubMed  CAS  Google Scholar 

  5. Ho YS, Gargano M, Cao J et al (1998) Reduced fertility in female mice lacking copper-zinc superoxide dismutase. J Biol Chem 273:7765–7769. doi:10.1074/jbc.273.13.7765

    Article  PubMed  CAS  Google Scholar 

  6. Matzuk MM, Dionne L, Guo Q et al (1998) Ovarian function in superoxide dismutase 1 and 2 knockout mice. Endocrinology 139:4008–4011. doi:10.1210/en.139.9.4008

    Article  PubMed  CAS  Google Scholar 

  7. McFadden SL, Ding D, Reaume AG et al (1999) Age-related cochlear hair cell loss is enhanced in mice lacking copper/zinc superoxide dismutase. Neurobiol Aging 20:1–8. doi:10.1016/S0197-4580(99)00018-4

    Article  PubMed  CAS  Google Scholar 

  8. Didion SP, Ryan MJ, Didion LA et al (2002) Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res 91:938–944. doi:10.1161/01.RES.0000043280.65241.04

    Article  PubMed  CAS  Google Scholar 

  9. Imamura Y, Noda S, Hashizume K et al (2006) Drusen, horoidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci USA 103:11282–11287. doi:10.1073/pnas.0602131103

    Article  PubMed  CAS  Google Scholar 

  10. Uchiyama S, Shimizu T, Shirasawa T (2006) CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. J Biol Chem 281:31713–31719. doi:10.1074/jbc.M603422200

    Article  PubMed  CAS  Google Scholar 

  11. Busuttil RA, Garcia AM, Cabrera C et al (2005) Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. Cancer Res 65:11271–11275. doi:10.1158/0008-5472.CAN-05-2980

    Article  PubMed  CAS  Google Scholar 

  12. Elchuri S, Oberley TD, Qi W et al (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24:367–380. doi:10.1038/sj.onc.1208207

    Article  PubMed  CAS  Google Scholar 

  13. Reaume AG, Elliott JL, Hoffman EK et al (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 3:43–47. doi:10.1038/ng0596-43

    Article  Google Scholar 

  14. Shefner JM, Reaume AG, Flood DG et al (1999) Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 53:239–1246

    Google Scholar 

  15. Yoshida T, Maulik N, Engelman RM et al (2000) Targeted disruption of the mouse Sod I gene makes the hearts vulnerable to ischemic reperfusion injury. Circ Res 86:264–269

    PubMed  CAS  Google Scholar 

  16. Ishii T, Matsuki S, Iuchi Y et al (2005) Accelerated impairment of spermatogenic cells in sod1-knockout mice under heat stress. Free Radic Res 39:697–705. doi:10.1080/10715760500130517

    Article  PubMed  CAS  Google Scholar 

  17. Yamanobe T, Okada F, Iuchi Y et al (2007) Deterioration of ischemia/reperfusion-induced acute renal failure in SOD1-deficient mice. Free Radic Res 41:200–207. doi:10.1080/10715760601038791

    Article  PubMed  CAS  Google Scholar 

  18. Iuchi Y, Okada F, Onuma K et al (2007) Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production. Biochem J 402:219–227. doi:10.1042/BJ20061386

    Article  PubMed  CAS  Google Scholar 

  19. Voetman AA, Loos JA, Roos D (1980) Changes in the levels of glutathione in phagocytosing human neutrophils. Blood 55:741–747

    PubMed  CAS  Google Scholar 

  20. Bilzer M, Lauterburg BH (1991) Glutathione metabolism in activated human neutrophils: stimulation of glutathione synthesis and consumption of glutathione by reactive oxygen species. Eur J Clin Invest 21:316–322. doi:10.1111/j.1365-2362.1991.tb01376.x

    Article  PubMed  CAS  Google Scholar 

  21. Carr AC, Winterbourn CC (1997) Oxidation of neutrophil glutathione and protein thiols by myeloperoxidase-derived hypochlorous acid. Biochem J 327:275–281

    PubMed  CAS  Google Scholar 

  22. Ogino T, Packer L, Maguire JJ (1997) Neutrophil antioxidant capacity during the respiratory burst: loss of glutathione induced by chloramines. Free Radic Biol Med 23:445–452. doi:10.1016/S0891-5849(97)00115-9

    Article  PubMed  CAS  Google Scholar 

  23. Bannai S, Tateishi N (1986) Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol 89:1–8. doi:10.1007/BF01870891

    Article  PubMed  CAS  Google Scholar 

  24. Bannai S, Kitamura E (1980) Transport interaction of l-cystine and l-glutamate in human diploid fibroblasts in culture. J Biol Chem 255:2372–2376

    PubMed  CAS  Google Scholar 

  25. Watanabe H, Bannai S (1987) Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med 165:628–640. doi:10.1084/jem.165.3.628

    Article  PubMed  CAS  Google Scholar 

  26. Sakakura Y, Sato H, Shiiya A et al (2007) Expression and function of cystine/glutamate transporter in neutrophils. J Leukoc Biol 81:974–982. doi:10.1189/jlb.0606385

    Article  PubMed  CAS  Google Scholar 

  27. Sato H, Tamba M, Ishii T et al (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 274:11455–11458. doi:10.1074/jbc.274.17.11455

    Article  PubMed  CAS  Google Scholar 

  28. Sasaki H, Sato H, Kuriyama-Matsumura K et al (2004) Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277:44765–44771. doi:10.1074/jbc.M208704200

    Article  Google Scholar 

  29. Bannai S, Sato H, Ishii T et al (1989) Induction of cystine transport activity in human fibroblasts by oxygen. J Biol Chem 264:18480–18484

    PubMed  CAS  Google Scholar 

  30. Sato H, Fujiwara K, Sagara J et al (1995) Induction of cystine transport activity in mouse peritoneal macrophages by bacterial lipopolysaccharide. Biochem J 310:547–551

    PubMed  CAS  Google Scholar 

  31. Sato H, Shiiya A, Kimata M et al (2005) Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem 280:37423–37429. doi:10.1074/jbc.M506439200

    Article  PubMed  CAS  Google Scholar 

  32. Otsu K, Ikeda Y, Fujii J (2004) Accumulation of manganese superoxide dismutase under metal-depleted conditions: proposed role for zinc ions in cellular redox balance. Biochem J 377:241–248. doi:10.1042/BJ20030935

    Article  PubMed  CAS  Google Scholar 

  33. Fujii T, Endo T, Fujii J et al (2002) Differential expression of glutathione reductase and cytosolic glutathione peroxidase, GPX1, in developing rat lungs and kidneys. Free Radic Res 36:1041–1049. doi:10.1080/1071576021000006725

    Article  PubMed  CAS  Google Scholar 

  34. Anderson ME (1985) Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol 113:548–555. doi:10.1016/S0076-6879(85)13073-9

    Article  PubMed  CAS  Google Scholar 

  35. Phelps DT, Deneke SM, Baxter DF et al (1989) Erythrocytes fail to induce glutathione in response to diethyl maleate or hyperoxia. Am J Physiol 257:L272–L276

    PubMed  CAS  Google Scholar 

  36. Raftos JE, Whillier S, Chapman BE et al (2007) Kinetics of uptake and deacetylation of N-acetylcysteine by human erythrocytes. Int J Biochem Cell Biol 39:1698–1706. doi:10.1016/j.biocel.2007.04.014

    Article  PubMed  CAS  Google Scholar 

  37. Blum J, Fridovich I (1985) Inactivation of glutathione peroxidase by superoxide radical. Arch Biochem Biophys 240:500–508. doi:10.1016/0003-9861(85)90056-6

    Article  PubMed  CAS  Google Scholar 

  38. Johnson RM, Goyetter G Jr, Ravindranath Y et al (2000) Red cells from glutathione peroxidase-1-deficient mice have nearly normal defenses against exogenous peroxides. Blood 96:1985–1988

    PubMed  CAS  Google Scholar 

  39. Low FM, Hampton MB, Peskin AV et al (2007) Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte. Blood 109:2611–2617. doi:10.1182/blood-2006-09-048728

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported, in part, by the 21st Century COE Program from the Japan Society for the Promotion of Science (JSPS).

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Authors and Affiliations

  1. Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata City, Yamagata, 990-9585, Japan

    Yoshihito Iuchi, Noriko Kibe, Satoshi Tsunoda, Futoshi Okada & Junichi Fujii

  2. Department of Bioresource Engineering, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata, 997-8555, Japan

    Shiro Bannai & Hideyo Sato

Authors
  1. Yoshihito Iuchi
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  2. Noriko Kibe
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  3. Satoshi Tsunoda
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Correspondence to Junichi Fujii.

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Iuchi, Y., Kibe, N., Tsunoda, S. et al. Deficiency of the cystine-transporter gene, xCT, does not exacerbate the deleterious phenotypic consequences of SOD1 knockout in mice. Mol Cell Biochem 319, 125–132 (2008). https://doi.org/10.1007/s11010-008-9885-3

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