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Oxidative stress in mitochondria

Decision to survival and death of neurons in neurodegenerative disorders

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Abstract

In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone, in human dopaminergic SH-SY5Y cells. In control cells, peroxynitrite nitrated proteins, especially the subunits of mitochondrial complex I, as 3-nitrotyrosine, suggesting that neurons are exposed to constant oxidative stress even under physiological conditions. SIN-1 and an inhibitor of proteasome, carbobenzoxy-l-isoleucyl-γ-t-butyl-l-analyl-l-leucinal (PSI), increased markedly the levels of nitrated proteins with concomitant induction of apoptosis in the cells. Rotenone induced mitochondrial dysfunction and accumulation and aggregation of proteins modified with acrolein, an aldehyde product of lipid peroxidation in the cells. At the same time, the activity of the 20S β-subunit of proteasome was reduced significantly, which degrades oxidative-modified protein. The mechanism was proved to be the result of the modification of the 20S β-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S β-subunit.

Increased oxidative stress caused by SIN-1 treatment induced a decline in the mitochondrial membrane potential, ΔΨm, and activated mitochondrial apoptotic signaling and induced cell death in SH-SY5Y cells. As another pathway, p38 mitogen-activated protein (MAP) kinase and exracellular signal-regulated kinase (ERK) mediated apoptosis induced by SIN-1. On the other hand, a series of neuroprotective propargylamine derivatives, including rasagiline [N-propargyl-1(R)aminoindan]and (−)deprenyl, intervened in the activation of apoptotic cascade by reactive oxygen species-reactive nitrogen species in mitochondria through stabilization of the membrane potential, ΔΨm. In addition, rasagiline induced antiapoptotic Bcl-2 and glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells, which was mediated by the ERK-nuclear factor (NF)-κB pathway. These results are discussed in relation to the interaction of oxidative stress and mitochondria in the regulation of neuronal death and survival in neurodegenerative diseases.

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References

  1. Halliwell B. (1992) Reactive oxygen species and the central nervous system. J. Neurochem. 59, 1609–1623.

    Article  PubMed  CAS  Google Scholar 

  2. Kroemer G., Dallaporta B., and Resch-Rigon M. (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu. Rev. Physiol. 60, 619–642.

    Article  PubMed  CAS  Google Scholar 

  3. Thompson C.G. (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462.

    Article  PubMed  CAS  Google Scholar 

  4. Yoritaka A., Hattori N., Uchida K., Tanaka M., Stadtman E.R., and Mizuno Y. (1996) Immuno-histochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc. Natl. Acad. Sci. USA 93, 2696–29701.

    Article  PubMed  CAS  Google Scholar 

  5. Sayre L.M., Zelasko D.A., Harris P.L.R., Perry G., Salomon R.G., and Smith M.A. (1997) 4-Hydroxynonenal-derived advanced lipid peroxydation and products are increased in Alzheimer’s disease. J. Neurochem. 68, 2092–2097.

    Article  PubMed  CAS  Google Scholar 

  6. Pedersen W.A., Fu W., Keller J.N., et al. (1998) Protein modification by the lipid peroxidation product 4-hydrononenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol. 44, 819–824.

    Article  PubMed  CAS  Google Scholar 

  7. Beckman J.S. (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chem. Res. Toxicol. 9, 836–844.

    Article  PubMed  CAS  Google Scholar 

  8. Halliwell B. (1997) What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? FEBS Lett. 411, 157–160.

    Article  PubMed  CAS  Google Scholar 

  9. White R., Brock T., Cjang L., et al. (1994) Superoxide and peroxynitrite in atherosclerosis. Proc. Natl. Acad. Sci. USA 91, 1044–1048.

    Article  PubMed  CAS  Google Scholar 

  10. Koppal T., Draake J., Yatin S., et al. (1999) Peroxynitrite-induced alternation in synaptosomal membrane proteins: insight into oxidative stress in Alzheimer’s disease. J. Neurochem. 72, 310–317.

    Article  PubMed  CAS  Google Scholar 

  11. Good P.F., Hsu A., Werner P., Perl D.P., and Olanow C.W. (1998) Protein nitration in Parkinson’s disease. J. Neuropathol. Exp. Neurol. 57, 338–342.

    PubMed  CAS  Google Scholar 

  12. Kato Y., Maruyama W., Naoi M., Hashizume Y., and Osawa T. (1998) Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain. FEBS Lett. 439, 231–234.

    Article  PubMed  CAS  Google Scholar 

  13. Chung K.K.K., Dawson V.L., and Dawson T.M. (2001) The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. TINS 24, S7-S14.

    PubMed  CAS  Google Scholar 

  14. Maruyama W., Kato Y., Yamamoto T., Oh-hashi K., Hashizume Y., and Naoi M. (2001) Peroxynitrite induced neuronal cell death in aging and age-associated disorders. J. Am. Aging Assoc. 24, 11–18.

    CAS  Google Scholar 

  15. Kato K., Ogino Y., Aoki T., Uchida K., Kawakishi S., and Osawa T. (1997) Phenolic anti-oxidants prevent peroxynitrite-derived collagen modification in vitro. J. Agric. Food Chem. 45, 3004–3009.

    Article  CAS  Google Scholar 

  16. Tanaka M., Miyabayashi S., Nishikimi M., et al. (1998) Extensive defects of mitochondrial electron-transfer chain in muscular cytochrome c oxidase deficiency. Pediatr. Res. 24, 447–454.

    Google Scholar 

  17. Mizuno Y., Ohta S., Tanaka M., et al. (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem. Biophys. Res. Commun. 163, 1450–1455.

    Article  PubMed  CAS  Google Scholar 

  18. Maruyama W., Takahashi T., and Naoi M. (1998) (−)Deprenyl protects human dopaminergic neuroblastoma SH-SY5Y cells from apoptosis induced by peroxynitrite and nitric oxide. J. Neurochem. 70, 2510–2515.

    Article  PubMed  CAS  Google Scholar 

  19. Oh-hashi K., Maruyama W., Yi H., Takahashi T., Naoi M., and Isobe M. (1999) Mitogen-activated protein kinase pathway mediates peroxynitrite-induced apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. Biochem. Biophys. Res. Commun. 263, 504–509.

    Article  PubMed  CAS  Google Scholar 

  20. Yamamoto T., Maruyama W., Kato Y., et al. (2002) Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondrial dysfunction and cell death of dopaminergic SH-SY5Y cells. J. Neural Transm. 109, 1–13.

    Article  PubMed  CAS  Google Scholar 

  21. Sharpe M.A. and Cooper C.E. (1998) Interaction of peroxynitrite with mitochondrial cytochrome oxidase. J. Biol. Chem. 273, 30,961–30,970.

    Article  CAS  Google Scholar 

  22. Iwatsubo T., Yamaguchi H., Fujikura M., et al. (1996) Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am. J. Pathol. 148, 1517–1529.

    PubMed  CAS  Google Scholar 

  23. Ii K., Ito H., Tanaka K., and Hirano A. (1997) Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative disease and the elderly. J. Neuropathol. Exp. Neurol. 56, 125–131.

    Article  PubMed  CAS  Google Scholar 

  24. Spillantini M.G., Schmidt M.L., Lee V.M.-Y., Trojanowski J.Q. Jakes R., and Goedert M. (1997) α-Synuclein in Lewy bodies. Nature 388, 837–840.

    Article  Google Scholar 

  25. Choi P., Osrerova-Golts N., Sparkman D., Cochran E., Lee J.M., and Wolozin B. (2000) Parkin is metabolized by the ubiquitin/proteasome system, Neuroreport 11, 2635–2638.

    Article  PubMed  CAS  Google Scholar 

  26. Shimura H., Schlossmacher M.G., Hattori N., et al. (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implication for Parkinson’s disease. Science 293, 263–269.

    Article  PubMed  CAS  Google Scholar 

  27. Tanaka Y., Engelender S., Igarashi S., et al. (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 10, 919–926.

    Article  PubMed  CAS  Google Scholar 

  28. Shamoto-Nagai M., Maruyama W., Kato Y., et al. (2003) An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. J. Neurosci. Res. 74, 589–597.

    Article  PubMed  CAS  Google Scholar 

  29. Betarbert R., Sherer T.B., MacKenzie G., Garcia-Osuna M., Panov A.V., and Greenamyre J.T. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306.

    Article  Google Scholar 

  30. Calingoson N.Y., Uchida K., and Gibson G.E. (1999) Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer’s disease. J. Neurochem. 72, 751–756.

    Article  Google Scholar 

  31. McNaught K.S.P. and Jenner P. (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci. Lett. 297, 191–194.

    Article  PubMed  CAS  Google Scholar 

  32. Hough R., Pratt G., and Rechsteiner M. (1987) Purification of two high molecular weight proteasomes from rabbit reticulocyte lysate. J. Biol. Chem. 262, 8303–8313.

    PubMed  CAS  Google Scholar 

  33. Okada K., Wangpoengtrakui C., Osawa T., Toyokuni S., Tanaka K., and Ucida K. (1992) 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. J. Biol. Chem. 274, 23,787–23,793.

    Google Scholar 

  34. Hortelano S., Alvarez A.M., and Bosca L. (1999) Nitric oxide induces tyrosine nitration and release of cytochrome c preceding an increase of mitochondrial transmembrane potential in macrophases. FASEB J. 13, 2311–2317.

    PubMed  CAS  Google Scholar 

  35. Cassina A.M., Hondara R., Souza J.M., et al. (2000) Cytochrome c nitration by peroxynitrite. J. Biol. Chem. 275, 21,409–21,415.

    Article  CAS  Google Scholar 

  36. Finucane D.M., Bossy-Wetzel E., Waterhouse N.J., Cotter T.G., and Green D.R. (1999) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibited by Bcl-xL. J. Biol. Chem. 274, 2225–2233.

    Article  PubMed  CAS  Google Scholar 

  37. Ghatan S., Larner S., Kinoshita Y., et al. (2000) P38 MAP kinase mediates Bax translocation in nitric oxide-induced apoptosis in neurons. J. Cell Biol. 150, 335–347.

    Article  PubMed  CAS  Google Scholar 

  38. Cheng A., Chan S.L., Milhavet O., Wang S., and Mattson M.P. (2001) P38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. J. Biol. Chem. 276, 43,320–43,327.

    CAS  Google Scholar 

  39. Naoi M. and Maruyama W. (2001) Future of neuroprotection in Parkinson’s disease. Parkin Related Dis. 8, 139–145.

    Article  CAS  Google Scholar 

  40. Ravina B.M., Fagan S.C., Hart R.G., et al. (2003) Neuroprotective agents for clinical trials in Parkinson’s disease. Neurology 60, 1234–1240.

    PubMed  CAS  Google Scholar 

  41. Mandel S., Grünblatt E., Riederer P., Gerlach M., Levites Y., and Youdim M.B.H. (2003) Neuroprotective strategies in Parkinson’s disease. CNS Drugs 17, 729–762.

    Article  PubMed  CAS  Google Scholar 

  42. Naoi M. and Maruyama W. (2000) Anti-apoptotic function of (−)-deprenyl, in Milestones in Monoamine Oxidase Research: Discovery of (−)-Deprenyl, Magyar K. and Vizi E.S., eds., Medicina Publishing House, Budapest, pp. 171–180.

    Google Scholar 

  43. Maruyama W., Takahashi T., Youdim M., and Naoi M. (2002) The anti-parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite inhuman dopaminergic neuroblastoma SH-SY5Y cells. J. Neural Transm. 109, 467–481.

    Article  PubMed  CAS  Google Scholar 

  44. Maruyama W., Boulton A.A., Davis B.A., Dostert P., and Naoi M. (2001) Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine. J. Neural Transm. 18, 11–24.

    Article  Google Scholar 

  45. Naoi M., Maruyama W., Akao Y., and Yi H. (2002) Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, and neuroprotection by propargylamines. J. Neural Transm. 102, 607–621.

    Article  Google Scholar 

  46. Maruyama W., Youdim M.B.H., and Naoi M. (2001) Antiapoptotic propertied of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann. NY Acad. Sci. 939, 320–329.

    Article  PubMed  CAS  Google Scholar 

  47. Maruyama W., Yi H., Takahashi T., et al. (2004) Neuroprotective function of R-(−)-1-(benzofuran-2-yl)-2-propargylamine, [R-(−)-BRAP] against apoptosis induced by N-methyl(R)salsolinol, and endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells. Life Sci. 75, 107–117.

    Article  PubMed  CAS  Google Scholar 

  48. Maruyama W., Akao Y., Youdim M.H., Davis B.A., and Naoi M. (2001) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehydes-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J. Neurochem. 78, 727–735.

    Article  PubMed  CAS  Google Scholar 

  49. Akao Y., Maruyama W., Shimizu S., et al. (2002) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propagyl-1(R)-aminoindan. J. Neurochem. 82, 913–923.

    Article  PubMed  CAS  Google Scholar 

  50. Akao Y., Maruyama W., Yi H., Shamoto-Nagai M., Youdim M.B.H., and Naoi M. (2002) An anti-Parkinson’s disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci. Lett. 326, 105–108.

    Article  PubMed  CAS  Google Scholar 

  51. Maruyama W., Nitta A., Shamoto-Nagai M., et al. (2004) N-Propargyl-1(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor. Neurochem. Int. 44, 393–400.

    Article  PubMed  CAS  Google Scholar 

  52. Carrillo M.C., Mimami C., Kitani K., et al. (2000) Enhancing effect of rasagiline on superoxide disputes and catalase activities in the dopaminergic system in the rats. Life Sci. 67, 577–585.

    Article  PubMed  CAS  Google Scholar 

  53. Biswas G., Anandatheerthavarada H.A., Zaidi M., and Avadhani N.G. (2003) Mitochondrial to nucleus stress signaling: a distinctive mechanism of NFkB/Rel activation through calcineurin-mediated inactivation of IkBβ. J. Cell Biol. 161, 507–519.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan

    Makoto Naoi, Hong Yi, Yukihiro Akao & Masashi Tanaka

  2. Department of Geriatrics, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan

    Wakako Maruyama & Masayo Shamoto-Nagai

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  1. Makoto Naoi
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  2. Wakako Maruyama
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  3. Masayo Shamoto-Nagai
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Correspondence to Makoto Naoi.

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Naoi, M., Maruyama, W., Shamoto-Nagai, M. et al. Oxidative stress in mitochondria. Mol Neurobiol 31, 81–93 (2005). https://doi.org/10.1385/MN:31:1-3:081

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  • DOI: https://doi.org/10.1385/MN:31:1-3:081

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