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Depressant Effect of Mitochondrial Respiratory Complex Inhibitors on Proteasome Inhibitor-Induced Mitochondrial Dysfunction and Cell Death in PC12 Cells

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The addition of rotenone (inhibitor of respiratory complex I), 3-nitropropionic acid (complex II inhibitor), harmine (inhibitor of complexes I and II) and cyclosporin A (CsA, an inhibitor of the mitochondrial permeability transition) reduced the nuclear damage, loss in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species and depletion of GSH in differentiated PC12 cells treated with MG132, a proteasome inhibitor. Meanwhile, rotenone, 3-nitropropionic acid and harmine did not affect the inhibitory effect of CsA or trifluoperazine (an inhibitor of the mitochondrial permeability transition and calmodulin antagonist) on the cytotoxicity of MG132. The results suggest that proteasome inhibition-induced mitochondrial dysfunction and cell injury may be attenuated by the inhibitions of respiratory chain complex I and II. The cytoprotective effect of the mitochondrial permeability transition prevention not appears to be modulated by respiratory complex inhibition.

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References

  1. R. Z. Orlowski (1999) ArticleTitleThe role of the ubiquitin-proteasome pathway in apoptosis Cell Death Differ. 6 303–313 Occurrence Handle10.1038/sj.cdd.4400505 Occurrence Handle10381632 Occurrence Handle1:CAS:528:DyaK1MXivFSqsrY%3D

    Article  PubMed  CAS  Google Scholar 

  2. L. Petrucelli T. M. Dawson (2004) ArticleTitleMechanism of neurodegenerative disease: Role of the ubiquitin proteasome system Ann. Med. 36 315–320 Occurrence Handle15224658 Occurrence Handle1:CAS:528:DC%2BD2cXksVKmtb0%3D Occurrence Handle10.1080/07853890410031948

    Article  PubMed  CAS  Google Scholar 

  3. K. S. McNaught P. Jenner (2001) ArticleTitleProteasomal function is impaired in substantia nigra in Parkinson’s disease Neurosci. Lett. 297 191–194 Occurrence Handle10.1016/S0304-3940(00)01701-8 Occurrence Handle11137760 Occurrence Handle1:CAS:528:DC%2BD3MXhsFejsb0%3D

    Article  PubMed  CAS  Google Scholar 

  4. J. H. Qiu A. Asai S. Chi N. Saito H. Hamada T. Kirino (2000) ArticleTitleProteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons J. Neurosci. 20 259–265 Occurrence Handle10627603 Occurrence Handle1:CAS:528:DC%2BD3cXhtF2iu7Y%3D

    PubMed  CAS  Google Scholar 

  5. C. S. Lee E. S. Han E. S. Park H. Bang (2005) ArticleTitleInhibition of MG132-induced mitochondrial dysfunction and cell death in PC12 cells by 3-morpholinosydnonimine Brain Res. 1036 18–26 Occurrence Handle10.1016/j.brainres.2004.12.036 Occurrence Handle15725397 Occurrence Handle1:CAS:528:DC%2BD2MXhslWktr4%3D

    Article  PubMed  CAS  Google Scholar 

  6. H. Kitagawa E. Tani H. Ikemoto I. Ozaki A. Nakano S. Omura (1999) ArticleTitleProteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells FEBS Lett. 443 181–186 Occurrence Handle10.1016/S0014-5793(98)01709-8 Occurrence Handle9989601 Occurrence Handle1:CAS:528:DyaK1MXmtVGgsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  7. D. H. Lee A. L. Goldberg (1998) ArticleTitleProteasome inhibitors: Valuable new tools for cell biologists Trends Cell Biol. 8 397–403 Occurrence Handle10.1016/S0962-8924(98)01346-4 Occurrence Handle9789328 Occurrence Handle1:CAS:528:DyaK1cXmvFWjtbc%3D

    Article  PubMed  CAS  Google Scholar 

  8. J. H. Bang E. S. Han I. Lim C. S. Lee (2004) ArticleTitleDifferential response of MG132 cytotoxicity against small cell lung cancer cells to changes in cellular GSH contents Biochem. Pharmacol. 68 659–666 Occurrence Handle10.1016/j.bcp.2004.04.010 Occurrence Handle15276073 Occurrence Handle1:CAS:528:DC%2BD2cXmtVWhsr4%3D

    Article  PubMed  CAS  Google Scholar 

  9. V. Stangi M. Lorenz S. Meiners A. Ludwig C. Bartsch M. Moobed A. Vietzke H. T. Kinkel G. Baumann K. Stangi (2004) ArticleTitleLong-term up-regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin-proteasome pathway FASEB 18 272–279

    Google Scholar 

  10. P. Jenner (2003) ArticleTitleOxidative stress in Parkinson’s disease Ann. Neurol. 53 IssueIDsuppl 3 S26–S38 Occurrence Handle12666096 Occurrence Handle1:CAS:528:DC%2BD3sXjtFGitLs%3D

    PubMed  CAS  Google Scholar 

  11. M. Crompton (1999) ArticleTitleThe mitochondrial permeability transition pore and its role in cell death Biochem. J. 341 233–249 Occurrence Handle10.1042/0264-6021:3410233 Occurrence Handle10393078 Occurrence Handle1:CAS:528:DyaK1MXltFCks74%3D

    Article  PubMed  CAS  Google Scholar 

  12. C. Fleury B. Mignotte J.-L. Vayssiere (2002) ArticleTitleMitochondrial reactive oxygen species in cell death signaling Biochimie 84 131–141 Occurrence Handle10.1016/S0300-9084(02)01369-X Occurrence Handle12022944 Occurrence Handle1:CAS:528:DC%2BD38XktVCqsr0%3D

    Article  PubMed  CAS  Google Scholar 

  13. J. Lotharius L. L. Dugan K. L. O’Malley (1999) ArticleTitleDistinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons J. Neurosci. 19 1284–1293 Occurrence Handle9952406 Occurrence Handle1:CAS:528:DyaK1MXhtFOhsrw%3D

    PubMed  CAS  Google Scholar 

  14. C. S. Lee J. H. Han Y. Y. Jang J. H. Song E. S. Han (2002) ArticleTitleDifferential effect of catecholamines and MPP+ on membrane permeability in brain mitochondria and cell viability in PC12 cells Neurochem. Int. 40 361–369 Occurrence Handle10.1016/S0197-0186(01)00069-9 Occurrence Handle11792467 Occurrence Handle1:CAS:528:DC%2BD38XktVOjtQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  15. J. J. Lemasters T. Qian L. C. Trost B. Herman W. E. Cascio C. A. Bradham D. A. Brenner A. L. Nieminen (1999) ArticleTitleConfocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death Biochem. Soc. Symp. 66 205–222 Occurrence Handle10989668 Occurrence Handle1:CAS:528:DC%2BD3cXkvVOksg%3D%3D

    PubMed  CAS  Google Scholar 

  16. R. D. Steinmetz B. Firla D. Steinhilber (2004) ArticleTitleInhibition of the functional expression of n-methyl-d-aspartate receptors in a stably transformed cell line by cyclosporine A Biochem. Pharmacol. 68 563–571 Occurrence Handle10.1016/j.bcp.2004.04.017 Occurrence Handle15242822 Occurrence Handle1:CAS:528:DC%2BD2cXlsFyls7Y%3D

    Article  PubMed  CAS  Google Scholar 

  17. E. N. Maciel G. S. Kaminski Schierle O. Hansson P. Brundin R. F. Castilho (2003) ArticleTitleCyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents Exp. Neurol. 183 430–437 Occurrence Handle10.1016/S0014-4886(03)00165-1 Occurrence Handle14552883 Occurrence Handle1:CAS:528:DC%2BD3sXnvVyktLw%3D

    Article  PubMed  CAS  Google Scholar 

  18. M. Azizian E. R. Ramenaden G. Shah C. Wilasrusmee D. Bruch D. S. Kittur (2004) ArticleTitleAugmentation of ischemia/reperfusion injury to endothelial cells by cyclosporine A Am. Surg. 70 438–442 Occurrence Handle15156953

    PubMed  Google Scholar 

  19. T. A. Seaton J. M. Cooper A. H. Schapira (1998) ArticleTitleCyclosporin inhibition of apoptosis induced by mitochondrial complex I toxins Brain Res. 809 12–17 Occurrence Handle10.1016/S0006-8993(98)00790-2 Occurrence Handle9795106 Occurrence Handle1:CAS:528:DyaK1cXms1Srurc%3D

    Article  PubMed  CAS  Google Scholar 

  20. C. P. Fall J. P. Bennett SuffixJr. (1998) ArticleTitleMPP+ induced SH-SY5Y apoptosis is potentiated by cyclosporin A and inhibited by aristolochic acid Brain Res. 811 143–146 Occurrence Handle10.1016/S0006-8993(98)00879-8 Occurrence Handle9804931 Occurrence Handle1:CAS:528:DyaK1cXmvFWhtrY%3D

    Article  PubMed  CAS  Google Scholar 

  21. G. U. Höglinger G. Carrard P. P. Michel F. Medja A. Lombes M. Ruberg B. Friguet E. C. Hirsch (2003) ArticleTitleDysfunction of mitochondrial complex I and the proteasome: Interactions between two biochemical deficits in a cellular model of Parkinson’s disease J. Neurochem. 86 1297–1307 Occurrence Handle12911637

    PubMed  Google Scholar 

  22. H. Sawada R. Kohno T. Kihara Y. Izumi N. Sakka M. Ibi M. Nakanishi T. Nakamizo K. Yamakawa H. Shibasaki N. Yamamoto A. Akaike M. Inden Y. Kitamura T. Taniguchi S. Shimohama (2004) ArticleTitleProteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions J. Biol. Chem. 279 10710–10719 Occurrence Handle10.1074/jbc.M405902200 Occurrence Handle14672949 Occurrence Handle1:CAS:528:DC%2BD2cXotVOgu7o%3D

    Article  PubMed  CAS  Google Scholar 

  23. W. G. Tatton R. M. E. Chalmers-Redman W. J. H. Ju M. Mammen G. W. Carlile A. W. Pong N. A. Tatton (2002) ArticleTitlePropargylamines induce antiapoptotic new protein synthesis in serum-and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells J. Pharmacol. Exp. Ther. 301 753–764 Occurrence Handle10.1124/jpet.301.2.753 Occurrence Handle11961082 Occurrence Handle1:CAS:528:DC%2BD38XjtlKisL8%3D

    Article  PubMed  CAS  Google Scholar 

  24. T. Mosmann (1983) ArticleTitleRapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays J. Immunol. Methods 65 55–63 Occurrence Handle10.1016/0022-1759(83)90303-4 Occurrence Handle6606682 Occurrence Handle1:STN:280:BiuD1cbgsFE%3D

    Article  PubMed  CAS  Google Scholar 

  25. F. A. Oberhammer M. Pavelka S. Sharma R. Tiefenbacher A. F. Purchio W. Bursch R. Schulte-Hermann (1992) ArticleTitleInduction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor β1 Proc. Natl. Acad. Sci. USA 89 5408–5412 Occurrence Handle1608949 Occurrence Handle1:CAS:528:DyaK38XksVGqu7o%3D

    PubMed  CAS  Google Scholar 

  26. J. S. Isenberg J. E. Klaunig (2000) ArticleTitleRole of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells Toxicol. Sci. 53 340–351 Occurrence Handle10.1093/toxsci/53.2.340 Occurrence Handle10696782 Occurrence Handle1:CAS:528:DC%2BD3cXhtF2ksL4%3D

    Article  PubMed  CAS  Google Scholar 

  27. W. Fu H. Luo S. Parthasarathy M. P. Mattson (1998) ArticleTitleCatecholamines potentiate amyloid β-peptide neurotoxicity: Involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis Neurobiol. Dis. 5 229–243 Occurrence Handle10.1006/nbdi.1998.0192 Occurrence Handle9848093 Occurrence Handle1:CAS:528:DyaK1cXnsFGntbY%3D

    Article  PubMed  CAS  Google Scholar 

  28. R. J. Klaveren Particlevan P. H. Hoet J. L. Pype M. Demedts B. Nemery (1997) ArticleTitleIncrease in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes Free Radic. Biol. Med. 22 525–534 Occurrence Handle8981045

    PubMed  Google Scholar 

  29. R. Albores E. J. Neafsey G. Drucker J. Z. Fields M. A. Collins (1990) ArticleTitleMitochondrial respiratory inhibition by N-methylated β-carboline derivatives structurally resembling N-methyl-4-phenylpyridine Proc. Natl. Acad. Sci. USA 87 9368–9372 Occurrence Handle2251279 Occurrence Handle1:CAS:528:DyaK3MXhtFKnu7o%3D

    PubMed  CAS  Google Scholar 

  30. J. Chandra A. Samali S. Orrenius (2000) ArticleTitleTriggering and modulation of apoptosis by oxidative stress Free Radic. Biol. Med. 29 323–333 Occurrence Handle10.1016/S0891-5849(00)00302-6 Occurrence Handle11035261 Occurrence Handle1:CAS:528:DC%2BD3cXnslWmt7s%3D

    Article  PubMed  CAS  Google Scholar 

  31. T. Kadota T. Yamaai Y. Saito Y. Akita S. Kawashima K. Moroi N. Inagaki K. Kadota (1996) ArticleTitleExpression of dopamine transporter at the tips of growing neurites of PC12 cells J. Histochem. Cytochem. 44 989–996 Occurrence Handle8773564 Occurrence Handle1:CAS:528:DyaK28XlsVOisLo%3D

    PubMed  CAS  Google Scholar 

  32. B. Wagenknecht M. Hermission P. Groscurth P. Liston P. H. Krammer M. Weller (2000) ArticleTitleProteasome inhibitor-induced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c release J. Neurochem. 75 2288–2297 Occurrence Handle10.1046/j.1471-4159.2000.0752288.x Occurrence Handle11080180 Occurrence Handle1:CAS:528:DC%2BD3cXotFKgurs%3D

    Article  PubMed  CAS  Google Scholar 

  33. M. Lee D. H. Hyun P. Jenner B. Halliwell (2001) ArticleTitleEffect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production J. Neurochem. 78 32–41 Occurrence Handle11432971 Occurrence Handle1:CAS:528:DC%2BD3MXltVymurY%3D

    PubMed  CAS  Google Scholar 

  34. S. Tada-Oikawa Y. Hiraku M. Kawanishi S. Kawanishi (2003) ArticleTitleMechanism for generation of hydrogen peroxide and change of mitochondrial membrane potential during rotenone-induced apoptosis Life Sci. 73 3277–3288 Occurrence Handle10.1016/j.lfs.2003.06.013 Occurrence Handle14561532 Occurrence Handle1:CAS:528:DC%2BD3sXotVyjsbs%3D

    Article  PubMed  CAS  Google Scholar 

  35. W. Pei A. K. F. Liou J. Chen (2003) ArticleTitleTwo caspase-mediated apoptotic pathways induced by rotenone toxicity in cortical neuronal cells FASEB 17 520–522 Occurrence Handle1:CAS:528:DC%2BD3sXitFejsrw%3D

    CAS  Google Scholar 

  36. M. F. Beal E. Brouillet B. G. Jenkins R. J. Ferrante N. W. Kowall J. M. Miller E. Storey R. Srivastava B. R. Rosen B. T. Hyman (1993) ArticleTitleNeurochemical and histologic characterization of striatal excitotoxic lesions by the mitochondrial toxin 3-nitropropionic acid J. Neurosci. 13 4181–4192 Occurrence Handle7692009 Occurrence Handle1:CAS:528:DyaK3sXms1CgtLc%3D

    PubMed  CAS  Google Scholar 

  37. T. R. Rosenstock A. C. Carvalho A. Jurkiewicz R. Frussa-Filho S. S. Smaili (2004) ArticleTitleMitochondrial calcium, oxidative stress and apoptosis in a neurodegenerative disease model induced by 3-nitropropionic acid J. Neurochem. 88 1220–1228 Occurrence Handle10.1046/j.1471-4159.2003.02250.x Occurrence Handle15009678 Occurrence Handle1:CAS:528:DC%2BD2cXhvFOru7s%3D

    Article  PubMed  CAS  Google Scholar 

  38. T. A. Seaton J. M. Cooper A. H. Schapira (1997) ArticleTitleFree radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors Brain Res. 777 110–118 Occurrence Handle9449419 Occurrence Handle1:CAS:528:DyaK2sXnvVSntLY%3D

    PubMed  CAS  Google Scholar 

  39. G. Benaim A. Villalobo (2002) ArticleTitlePhosphorylation of calmodulin. Functional implications Eur. J. Biochem. 269 3619–3631 Occurrence Handle10.1046/j.1432-1033.2002.03038.x Occurrence Handle12153558 Occurrence Handle1:CAS:528:DC%2BD38XmsVSit7w%3D

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, College of Medicine, Chung-Ang University, 156-756, Seoul, South Korea

    Sun-Joo Lee, Eun Sook Han & Chung Soo Lee

  2. Department of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea

    Young Chul Youn

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  1. Sun-Joo Lee
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Lee, SJ., Youn, Y.C., Han, E.S. et al. Depressant Effect of Mitochondrial Respiratory Complex Inhibitors on Proteasome Inhibitor-Induced Mitochondrial Dysfunction and Cell Death in PC12 Cells. Neurochem Res 30, 1191–1200 (2005). https://doi.org/10.1007/s11064-005-8158-8

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