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Mitochondrial Dysfunction Enhances Susceptibility to Oxidative Stress by Down-Regulation of Thioredoxin in Human Neuroblastoma Cells

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Abstract

Increasing evidence suggests that Alzheimer’s disease is associated with mitochondrial dysfunction and oxidative damage. To develop a cellular model of Alzheimer’s disease, we investigated the effects of thioredoxin (Trx) expression in the response to mitochondrial dysfunction-enhanced oxidative stress in the SH-SY5Y human neuroblastoma cells. Treatment of SH-SY5Y cells with 15 mM of NaN3, an inhibitor of cytochrome c oxidase (complex IV), led to alteration of mitochondrial membrane potential but no significant changes in cell viability. Therefore, cells were first treated with 15 mM NaN3 to induce mitochondrial dysfunction, then, exposed to different concentrations of H2O2. Cell susceptibility was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and morphological observation. Expressions of Trx mRNA and protein were determined by RT-PCR; and Western-blot analysis, respectively. It was found that the SH-SY5Y cells with mitochondrial impairment had lower levels of Trx mRNA and protein, and were significantly more vulnerable than the normal cells after exposure to H2O2 while no significant changes of Trx mRNA and protein in SH-SY5Y cells exposed to H2O2 but without mitochondrial complex IV inhibition. These results, together with our previous study in primary cultured neurons, demonstrated that the increased susceptibility to oxidative stress is induced at least in part by the down-regulation of Trx in SH-SY5Y human neuroblastoma cells with mitochondrial impairment and also suggest the mitochondrial dysfunction-enhanced oxidative stress could be used as a cellular model to study the mechanisms of Alzheimer’s disease and agents for prevention and treatment.

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References

  1. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    PubMed  CAS  Google Scholar 

  2. Onyango IG, Khan SM (2006) Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer’s disease. Curr Alzheimer Res 3:339–349

    Article  PubMed  CAS  Google Scholar 

  3. Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L (2006) Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 10:59–73

    PubMed  CAS  Google Scholar 

  4. Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith VA (2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 9:147–153

    PubMed  Google Scholar 

  5. Ohta S, Ohsawa I (2006) Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease: on defects in the cytochrome c oxidase complex and aldehyde detoxification. J Alzheimers Dis 9:155–166

    PubMed  Google Scholar 

  6. Nunomura A, Perry G, Zhang J, Montine TJ, Takeda A, Chiba S, Smith MA (1999) RNA oxidation in Alzheimer and Parkinson diseases. J Anti Aging Med 2:227–230

    CAS  Google Scholar 

  7. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187

    PubMed  CAS  Google Scholar 

  8. Cottrell DA, Borthwick GM, Johnson MA, Ince PG, Turnbull DM (2002) The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer’s disease. Neuropathol Appl Neurobiol 28:390–396

    Article  PubMed  CAS  Google Scholar 

  9. Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2:246–253

    Article  PubMed  CAS  Google Scholar 

  10. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716

    PubMed  CAS  Google Scholar 

  11. Ames BN, Shigenaga MK, Hagen TM (1995) Mitochondrial decay in aging. Biochim Biophys Acta 1271:165–170

    PubMed  Google Scholar 

  12. Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    PubMed  CAS  Google Scholar 

  13. Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778

    Article  PubMed  CAS  Google Scholar 

  14. Moreira PI, Siedlak SL, Aliev G, Zhu X, Cash AD, Smith MA, Perry G (2005) Oxidative stress mechanisms and potential therapeutics in Alzheimer disease. J Neural Transm 112:921–932

    Article  PubMed  CAS  Google Scholar 

  15. Lowell BB, Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404:652–660

    PubMed  CAS  Google Scholar 

  16. Gao J, Zhu ZR, Ding HQ, Qian Z, Zhu L, Ke Y (2007) Vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin. Neurochem Int 50:379–385

    Article  PubMed  CAS  Google Scholar 

  17. Gao J, Sun HY, Zhu ZR, Ding Z, Zhu L (2005) Antioxidant effects of dehydroepiandrosterone are related to up-regulation of thioredoxin in SH-SY5Y cells. Acta Biochim Biophys Sin (Shanghai) 37:119–125

    Article  CAS  Google Scholar 

  18. Wadia JS, Chalmers-Redman RM, Ju WJ, Carlile GW, Phillips JL, Fraser AD, Tatton WG (1998) Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal: time course and modification by (-)-deprenyl. J Neurosci 18:932–947

    PubMed  CAS  Google Scholar 

  19. Windle HJ, Fox A, Ni Eidhin D, Kelleher D (2000) The thioredoxin system of Helicobacter pylori. J Biol Chem 275:5081–5089

    Article  PubMed  CAS  Google Scholar 

  20. Chandrasekaran K, Giordano T, Brady DR, Stoll J, Martin LJ, Rapoport SI (1994) Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res Mol Brain Res 24:336–340

    Article  PubMed  CAS  Google Scholar 

  21. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr, Davis RE, Parker WD Jr (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49:918–925

    PubMed  CAS  Google Scholar 

  22. Kish SJ, Mastrogiacomo F, Guttman M, Furukawa Y, Taanman JW, Dozic S, Pandolfo M, Lamarche J, DiStefano L, Chang LJ (1999) Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer’s disease and in hereditary spinocerebellar ataxia disorders: a nonspecific change? J Neurochem 72:700–707

    Article  PubMed  CAS  Google Scholar 

  23. Sastre J, Pallardo FV, Vina J (2000) Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49:427–435

    Article  PubMed  CAS  Google Scholar 

  24. Lovell MA, Xie C, Gabbita SP, Markesbery WR (2000) Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer’s disease brain. Free Radic Biol Med 28:418–427

    Article  PubMed  CAS  Google Scholar 

  25. Shibata T, Yamada T, Ishii T, Kumazawa S, Nakamura H, Masutani H, Yodoi J, Uchida K (2003) Thioredoxin as a molecular target of cyclopentenone prostaglandins. J Biol Chem 278:26046–26054

    Article  PubMed  CAS  Google Scholar 

  26. Masutani H, Bai J, Kim YC, Yodoi J (2004) Thioredoxin as a neurotrophic cofactor and an important regulator of neuroprotection. Mol Neurobiol 29:229–242

    Article  PubMed  CAS  Google Scholar 

  27. Ju TC, Chen SD, Liu CC, Yang DI (2005) Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity. Free Radic Biol Med 38:938–949

    Article  PubMed  CAS  Google Scholar 

  28. Sagara JI, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial cells. J Neurochem 61:1672–1676

    Article  PubMed  CAS  Google Scholar 

  29. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52:1–6

    Article  PubMed  CAS  Google Scholar 

  30. Bennett MC, Diamond DM, Stryker SL, Parks JK, Parker WD Jr (1992) Cytochrome oxidase inhibition: a novel animal model of Alzheimer’s disease. J Geriatr Psychiatry Neurol 5:93–101

    PubMed  CAS  Google Scholar 

  31. Szabados T, Dul C, Majtenyi K, Hargitai J, Penzes Z, Urbanics R (2004) A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations. Behav Brain Res 154:31–40

    Article  PubMed  CAS  Google Scholar 

  32. Calabrese V, Bates TE, Stella AM (2000) NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. Neurochem Res 25:1315–1341

    Article  PubMed  CAS  Google Scholar 

  33. Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by Excellent Young Teachers Program of MOE and grants from Jiangsu University (07JDG012).

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Authors and Affiliations

  1. School of Pharmacy, Jiangsu University, Zhenjiang, 212013, P.R. China

    Hongqun Ding, Jing Gao & Yuyun Xiong

  2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, 210093, P.R. China

    Hongqun Ding, Jing Gao & Zengrong Zhu

  3. Institute for Brain Aging and Dementia, University of California, Irvine, CA, 92697-4540, USA

    Jiankang Liu

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  1. Hongqun Ding
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Correspondence to Jing Gao.

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Ding, H., Gao, J., Zhu, Z. et al. Mitochondrial Dysfunction Enhances Susceptibility to Oxidative Stress by Down-Regulation of Thioredoxin in Human Neuroblastoma Cells. Neurochem Res 33, 43–50 (2008). https://doi.org/10.1007/s11064-007-9405-y

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  • DOI: https://doi.org/10.1007/s11064-007-9405-y

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