Advertisement

Biochemistry (Moscow)

, Volume 75, Issue 2, pp 123–129 | Cite as

Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants — the “Skulachev-ion” derivatives

  • D. S. Izyumov
  • L. V. Domnina
  • O. K. Nepryakhina
  • A. V. Avetisyan
  • S. A. Golyshev
  • O. Y. Ivanova
  • M. V. Korotetskaya
  • K. G. Lyamzaev
  • O. Y. Pletjushkina
  • E. N. Popova
  • B. V. ChernyakEmail author
Article

Abstract

Production of reactive oxygen species (ROS) in mitochondria was studied using the novel mitochondria-targeted antioxidants (SkQ) in cultures of human cells. It was shown that SkQ rapidly (1–2 h) and selectively accumulated in mitochondria and prevented oxidation of mitochondrial components under oxidative stress induced by hydrogen peroxide. At nanomolar concentrations, SkQ inhibited oxidation of glutathione, fragmentation of mitochondria, and translocation of Bax from cytosol into mitochondria. The last effect could be related to prevention of conformational change in the adenine nucleotide transporter, which depends on oxidation of critical thiols. Mitochondria-targeted antioxidants at nanomolar concentrations prevented accumulation of ROS and cell death under oxidative stress. These effects required 24 h or more (depending on the cell type) preincubation, and this was not related to slow induction of endogenous antioxidant systems. It is suggested that SkQ slowly accumulates in a small subpopulation of mitochondria that have decreased membrane potential and produce the major part of ROS under oxidative stress. This population was visualized in the cells using potential-sensitive dye. The possible role of the small fraction of “bad” mitochondria in cell physiology is discussed.

Key words

oxidative stress mitochondria-targeted antioxidants SkQ mitochondria apoptosis 

Abbreviations

ANT

adenine nucleotide translocator

CM-DCF-DA

5-(-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate

C12TPP

dodecyltriphenylphosphonium

FCCP

carbonyl cyanide p-trifluoromethoxyphenylhydrazone

ROS

reactive oxygen species

SkQ

cationic derivative of plastoquinone

SkQ1

10-(6′-plastoquinonyl) decyltriphenylphosphonium

SkQR1

10-(6′-plastoquinonyl) decylrhodamine 19

TMRM

tetramethylrhodamine methyl ester

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

10541_2010_9163_MOESM1_ESM.pdf (262 kb)
Appendix (PDF 262 KB)

References

  1. 1.
    Liberman, E. A., Topali, V. P., Tsofina, L. M., Jasaitis, A. A., and Skulachev, V. P. (1969) Nature, 222, 1076–1078.CrossRefPubMedGoogle Scholar
  2. 2.
    Cocheme, H. M., Kelso, G. F., James, A. M., Ross, M. F., Trnka, J., Mahendiran, T., Asin-Cayuela, J., Blaikie, F. H., Manas, A. R., Porteous, C. M., Adlam, V. J., Smith, R. A., and Murphy, M. P. (2007) Mitochondrion, 7, 94–102.CrossRefGoogle Scholar
  3. 3.
    Armstrong, J. S. (2008) Antioxid. Redox. Signal., 10, 575–578.CrossRefPubMedGoogle Scholar
  4. 4.
    Antonenko, Y. N., Roginsky, V. A., Pashkovskaya, A. A., Rokitskaya, T. I., Kotova, E. A., Zaspa, A. A., Chernyak, B. V., and Skulachev, V. P. (2008) J. Membr. Biol., 222, 141–149.CrossRefPubMedGoogle Scholar
  5. 5.
    Skulachev, V. P., Anisimov, V. N., Antonenko, Y. N., Bakeeva, L. E., Chernyak, B. V., Erichev, V. P., Filenko, O. F., Kalinina, N. I., Kapelko, V. I., Kolosova, N. G., Kopnin, B. P., Korshunova, G. A., Lichinitser, M. R., Obukhova, L. A., Pasyukova, E. G., Pisarenko, O. I., Roginsky, V. A., Ruuge, E. K., Senin, I. I., Severina, I. I., Skulachev, M. V., Spivak, I. M., Tashlitsky, V. N., Tkachuk, V. A., Vyssokikh, M. Y., Yaguzhinsky, L. S., and Zorov, D. B. (2009) Biochim. Biophys. Acta, 1787, 437–461.CrossRefPubMedGoogle Scholar
  6. 6.
    Antonenko, Y. N., Avetisyan, A. V., Bakeeva, L. E., Chernyak, B. V., Chertkov, V. A., Domnina, L. V., Ivanova, O. Y., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Pletjushkina, O. Y., Pustovidko, A. V., Roginsky, V. A., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Severina, I. I., Simonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sumbatyan, N. V., Sviryaeva, I. V., Tashlitsky, V. N., Vassiliev, J. M., Vyssokikh, M. Y., Yaguzhinsky, L. S., Zamyatnin, A. A., Jr., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1273–1287.PubMedGoogle Scholar
  7. 7.
    Anisimov, V. N., Bakeeva, L. E., Egormin, P. A., Filenko, O. F., Isakova, E. F., Manskikh, V. N., Mikhelson, V. M., Panteleeva, A. A., Pasyukova, E. G., Pilipenko, D. I., Piskunova, T. S., Popovich, I. G., Roshchina, N. V., Rybina, O. Y., Saprunova, V. B., Samoylova, T. A., Semenchenko, A. V., Skulachev, M. V., Spivak, I. M., Tsybul’ko, E. A., Tyndyk, M. L., Vyssokikh, M. Y., Yurova, M. N., Zabezhinsky, M. A., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1329–1342.PubMedGoogle Scholar
  8. 8.
    Bakeeva, L. E., Barskov, I. V., Egorov, M. V., Isaev, N. K., Kapelko, V. I., Kazachenko, A. V., Kirpatovsky, V. I., Kozlovsky, S. V., Lakomkin, V. L., Levina, S. B., Pisarenko, O. I., Plotnikov, E. Y., Saprunova, V. B., Serebryakova, L. I., Skulachev, M. V., Stelmashook, E. V., Studneva, I. M., Tskitishvili, O. V., Vasilyeva, A. K., Victorov, I. V., Zorov, D. B., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1288–1299.PubMedGoogle Scholar
  9. 9.
    Neroev, V. V., Archipova, M. M., Bakeeva, L. E., Fursova, A. Z., Grigorian, E. N., Grishanova, A. Y., Iomdina, E. N., Ivashchenko, Z., Katargina, L. A., Khoroshilova-Maslova, I. P., Kilina, O. V., Kolosova, N. G., Kopenkin, E. P., Korshunov, S. S., Kovaleva, N. A., Novikova, Y. P., Philippov, P. P., Pilipenko, D. I., Robustova, O. V., Saprunova, V. B., Senin, I. I., Skulachev, M. V., Sotnikova, L. F., Stefanova, N. A., Tikhomirova, N. K., Tsapenko, I. V., Shchipanova, A. I., Zinovkin, R. A., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1317–1328.PubMedGoogle Scholar
  10. 10.
    Pletjushkina, O. Y., Fetisova, E. K., Lyamzaev, K. G., Ivanova, O. Y., Domnina, L. V., Vyssokikh, M. Y., Pustovidko, A. V., Vasiliev, J. M., Murphy, M. P., Chernyak, B. V., and Skulachev, V. P. (2005) Cell Death Differ., 12, 1442–1444.CrossRefPubMedGoogle Scholar
  11. 11.
    Chernyak, B. V., Izyumov, D. S., Lyamzaev, K. G., Pashkovskaya, A. A., Pletjushkina, O. Y., Antonenko, Y. N., Sakharov, D. V., Wirtz, K. W., and Skulachev, V. P. (2006) Biochim. Biophys. Acta, 1757, 525–534.CrossRefPubMedGoogle Scholar
  12. 12.
    Saini, H. K., Machackova, J., and Dhalla, N. S. (2004) Antioxid. Redox. Signal., 6, 393–404.CrossRefPubMedGoogle Scholar
  13. 13.
    Skulachev, V. P. (2001) Trends Biochem. Sci., 26, 23–29.CrossRefPubMedGoogle Scholar
  14. 14.
    Benard, G., and Karbowski, M. (2009) Semin. Cell Dev. Biol., 20, 365–374.CrossRefPubMedGoogle Scholar
  15. 15.
    Adams, J. M., and Cory, S. (2007) Curr. Opin. Immunol., 19, 488–496.CrossRefPubMedGoogle Scholar
  16. 16.
    Crompton, M. (2000) J. Physiol., 15, 11–21.CrossRefGoogle Scholar
  17. 17.
    Vyssokikh, M. Y., and Brdiczka, D. (2003) Acta Biochim. Pol., 50, 389–404.PubMedGoogle Scholar
  18. 18.
    Halestrap, A. P., and Brennerb, C. (2003) Curr. Med. Chem., 10, 1507–1525.CrossRefPubMedGoogle Scholar
  19. 19.
    Klingenberg, M. (2008) Biochim. Biophys. Acta, 1778, 1978–2021.CrossRefPubMedGoogle Scholar
  20. 20.
    Sheridan, C., Delivani, P., Cullen, S. P., and Martin, S. J. (2008) Mol. Cell, 22, 570–585.CrossRefGoogle Scholar
  21. 21.
    Kuznetsov, A. V., and Margreiter, R. (2009) Int. J. Mol. Sci., 10, 1911–1929.CrossRefPubMedGoogle Scholar
  22. 22.
    Lemasters, J. J., and Ramshesh, V. K. (2007) Methods Cell Biol., 80, 283–295.CrossRefPubMedGoogle Scholar
  23. 23.
    Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E., and Shirihai, O. S. (2008) EMBO J., 27, 433–446.CrossRefPubMedGoogle Scholar
  24. 24.
    Belousov, V. V., Fradkov, A. F., Lukyanov, K. A., Staroverov, D. B., Shakhbazov, K. S., Terskikh, A. V., and Lukyanov, S. (2006) Nat. Methods, 3, 281–286.CrossRefPubMedGoogle Scholar
  25. 25.
    Zorov, D. B., Filburn, C. R., Klotz, L. O., Zweier, J. L., and Sollott, S. J. (2000) J. Exp. Med., 192, 1001–1014.CrossRefPubMedGoogle Scholar
  26. 26.
    Skulachev, V. P. (2005) IUBMB Life, 57, 305–310.CrossRefPubMedGoogle Scholar
  27. 27.
    Storz, P. (2007) Trends Cell Biol., 17, 13–18.CrossRefPubMedGoogle Scholar
  28. 28.
    Skulachev, V. P., and Longo, V. D. (2005) Ann. N. Y. Acad. Sci., 1057, 145–164.CrossRefPubMedGoogle Scholar
  29. 29.
    Harman, D. (1956) J. Gerontol., 11, 298–300.PubMedGoogle Scholar
  30. 30.
    Greaves, L. C., Beadle, N. E., Taylor, G. A., Commane, D., Mathers, J. C., Khrapko, K., and Turnbull, D. M. (2009) Aging Cell, 8, 566–572.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2010

Authors and Affiliations

  • D. S. Izyumov
    • 1
  • L. V. Domnina
    • 1
  • O. K. Nepryakhina
    • 1
  • A. V. Avetisyan
    • 1
  • S. A. Golyshev
    • 1
  • O. Y. Ivanova
    • 1
  • M. V. Korotetskaya
    • 1
  • K. G. Lyamzaev
    • 1
  • O. Y. Pletjushkina
    • 1
  • E. N. Popova
    • 1
  • B. V. Chernyak
    • 1
    Email author
  1. 1.Belozersky Institute of Physico-Chemical Biology and Mitoengineering CenterLomonosov Moscow State UniversityMoscowRussia

Personalised recommendations