Molecular mechanisms of transformation of SkQ mitotropic quinones and the search for new approaches to creation of selective free radical traps

Abstract

Features of the mechanism of action of positively charged benzoquinone derivatives (SkQ), which are the analogs of coenzyme Q (I), plastoquinone (II), and tocopherol (III), are discussed. It is usually considered that the main target of these compounds is mitochondria, where they accumulate due to the positive charge of the molecule. In the present work, it is shown with model systems that the reduced forms of compounds (I–III) under certain conditions can transform into electrically neutral cyclic zwitterions, which theoretically can escape from the matrix of energized mitochondria against the concentration gradient. A weak uncoupling effect of molecules I–III has been found on mitochondria. Its existence is in agreement with the abovementioned transformation of positively charged hydroquinones of type Ia–IIIa into electrically neutral molecules. The data obtained with model systems suggest that the target of SkQ hydroquinones as free radical traps may be not only mitochondria but also biochemical systems of the cytoplasm. Due to the presence of a large number of reactive oxygen species (ROS)-dependent signal systems in a cell, the functioning of cytoplasmic systems might be disturbed under the action of antioxidants. The problem of selective effect of antioxidants is discussed in detail in the present work, and a functional diagram of selective decrease of the “background level” of ROS based on differences in the intensity of background and “signal” ROS fluxes is considered.

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Abbreviations

CoQ:

coenzyme Q

DQ:

duroquinone

MitoQ:

2,3-dimethoxy-5-methyl-1,4-quinone-6-decylbenzene triphenylphosphonium chloride

MitoQH2 :

2,3-dimethoxy-5-methyl-1,4-diol-6-decylbenzene triphenylphosphonium chloride

ROS:

reactive oxygen species

SkQ1:

2,3-dimethyl-1,4-quinone-5-decylbenzene triphenylphosphonium chloride

SkQ1H2 :

2,3-dimethyl-1,4-diol-5-decylbenzene triphenylphosphonium chloride

SkQ3:

2,3,5-dimethyl-1,4-quinone-6-decylbenzene triphenylphosphonium chloride

SkQ3H2 :

2,3,5-dimethyl-1,4-diol-6-decylbenzene triphenylphosphonium chloride

TPP+ :

triphenylphosphonium cation

References

  1. 1.

    Antonenko, Yu. N., Avetisyan, A. V., Bakeyeva, L. E., Chernyak, B. V., Chertkov, V. A., Domnina, L. V., Ivanova, O. Yu., Izyumov, D. S., Khaylova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzayev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Pletjushkina, O. Yu., 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., Sviryayeva, I. V., Tashlitsky, V. N., Vasilyev, J. M., Vyssokikh, M. Yu., Yaguzhinsky, L. S., Zamyatnin, A. A., Jr., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1273–1287.

    CAS  Article  Google Scholar 

  2. 2.

    Murphy, M. P., and Smith, R. (2007) Annu. Rav. Pharmacol. Toxicol., 47, 629–656.

    CAS  Article  Google Scholar 

  3. 3.

    Skulachev, V. P. (2007) Biochemistry (Moscow), 72, 1385–1396.

    CAS  Article  Google Scholar 

  4. 4.

    James, A. M., Cocheme, H. M., Smith, R. A., and Murphy, M. P. (2005) J. Biol. Chem., 280, 21259–21312.

    Article  Google Scholar 

  5. 5.

    Koopman, W. J., Verkaart, S., Visch, H. J., van der Westhuizen, F. H., Murphy, M. P., van der Heuvel, L. W., Smeitink, J. A., and Willems, P. H. (2005) Am. J. Physiol. Cell Physiol., 288, 1440–1450.

    Article  Google Scholar 

  6. 6.

    Kargin, V. I., Motovilov, K. A., Vyssokikh, M. Yu., and Yaguzhinsky, L. S. (2008) Biol. Membr. (Moscow), 25, 34–40.

    CAS  Google Scholar 

  7. 7.

    Zhu, Q. S., Berden, J. A., de Vries, S., Folkers, K., Porter, T., and Slater, E. C. (1982) Biochim. Biophys. Acta, 680, 69–79.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Forman, H. J., Fukuto, J. M., and Torres, M. (2004) Am. J. Physiol. Cell. Physiol., 287, 246–256.

    Article  Google Scholar 

  9. 9.

    Moskovitz, J., Berlett, B. S., Poston, J. M., and Stadtman, E. R. (1997) Proc. Natl. Acad. Sci. USA, 94, 9585–9589.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Sen, S. K. (1998) Biochem. Pharm., 55, 1747–1758.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Pletjushkina, O. Y., Fetisova, E. K., Lyamzaev, K. G., Ivanova, O. Y., Domnina, L. V., Vyssokikh, M. Y., Pustovidko, A. V., Alexeevski, A. V., Alexeevski, D. A., Vasiliev, J. M., Murphy, M. P., Chernyak, B. V., and Skulachev, V. P. (2006) Biochemistry (Moscow), 71, 60–67.

    CAS  Article  Google Scholar 

  12. 12.

    Gasch, A. P., Spellman, P. T., Kao, C. M., Carmel-Harel, O., Eisen, M. B., Storz, G., Botstein, D., and Brown, P. O. (2000) Mol. Biol. Cell., 11, 4241–4257.

    CAS  PubMed  Google Scholar 

  13. 13.

    Zheng, M., Aslund, F., and Storz, G. (1998) Science, 279, 1718–1721.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Na, H. K., and Surh, Y. J. (2006) Mol. Carcinolog., 45, 368–380.

    CAS  Article  Google Scholar 

  15. 15.

    Wu, R. F., and Terada, L. S. (2006) Sci. STKE, 332, 12.

    Google Scholar 

  16. 16.

    Werner, E. (2004) J. Cell Sci., 117, 143–153.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Ohba, M., Shibanuba, M., Kuroki, T., and Nose, K. (1994) J. Cell Biol., 126, 1079–1088.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Wood, Z., Poole, L., and Karplus, A. (2003) Science, 300, 650–653.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Peshenko, I. V., and Shichi, H. (1999) Free Rad. Biol. Med., 31, 292–303.

    Article  Google Scholar 

  20. 20.

    Butterfield, L. H., Merino, A., Golub, S. H., and Shau, H. (1999) Science, 31, 292–303.

    Google Scholar 

  21. 21.

    Bystrova, M. F., and Budanova, E. N. (2007) Biol. Membr. (Moscow), 24, 115–125.

    CAS  Google Scholar 

  22. 22.

    Bae, Y. S., Kang, S. W., Seo, M. S., Baines, I. C., Tekle, E., Chock, P. B., and Rhee, S. G. (1997) J. Biol. Chem., 272, 217–221.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lee, S. R., Yang, K. S., Know, J., Lee, S., Jeong, W., and Rhee, S. G. (1998) J. Biol. Chem., 273, 15366–15372.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Sattler, M., Winkler, T., Verma, S., Byrne, S. H., Shrikhande, G., Salgia, R., and Griffin, J. D. (1999) Blood, 93, 2928–2935.

    CAS  PubMed  Google Scholar 

  25. 25.

    Belmonte, M. A., Santos, M. F., Kihara, A. H., Yan, C. Y. I., and Hamassaki, D. E. (2006) Invest. Ophthalmol. Vis. Sci., 47, 1193–1200.

    Article  PubMed  Google Scholar 

  26. 26.

    Deshpande, S. S., Qi, B., Park, Y. C., and Irani, K. (2003) Arterioscler. Thromb. Vasc. Biol., 23, 1–6.

    Article  Google Scholar 

  27. 27.

    Birukov, K. G., Birukova, A. A., Dudek, S. M., Verin, A. D., Crow, M. T., Zhan, X., DePaola, N., and Garcia, J. G. N. (2002) Am. J. Respir. Cell Mol. Biol., 26, 453–464.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hordijk, P. L. (2006) Circ. Res., 98, 453–462.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Puceat, M. (2005) Antioxid. Redox. Signal., 7, 1435–1439.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Johnson, D., and Lardy, H. (1967) Meth. Enzymol., 10, 94–96.

    CAS  Article  Google Scholar 

  31. 31.

    Schwartz, J. E., and Durham, B. C. (1979) Ann. Clin. Lab. Sci., 9, 139–143.

    CAS  PubMed  Google Scholar 

  32. 32.

    Karas, M., Bachmann, D., Bahr, D., and Hillenkamp, F. (1987) Int. J. Mass Spectrom. Ion Proc., 78, 53–68.

    CAS  Article  Google Scholar 

  33. 33.

    Korshunov, S. S., Korkina, O. V., Ruuge, E. K., Skulachev, V. P., and Starkov, A. A. (1998) FEBS Lett., 432, 215–218.

    Article  Google Scholar 

  34. 34.

    Ovchinnikov, Yu. A., Ivanov, V. T., and Shkrob, A. M. (1974) Membrane-Active Chelators [in Russian], Nauka, Moscow.

    Google Scholar 

  35. 35.

    Blaikie, F. H., Brown, S. E., Samuelsson, L. M., Brand, M. D., Smith, R. A. J., and Murphy, P. (2006) Biosci. Rep., 26, 231–243.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    James, A. M., Smith, R. A., and Murphy, M. P. (2004) Arch. Biochem. Biophys., 423, 47–56.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Burlakova, E. B., Krashakov, S. A., and Khrapova, N. G. (1998) Biol. Membr. (Moscow), 15, 137–167.

    CAS  Google Scholar 

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Correspondence to L. S. Yaguzhinsky.

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Original Russian Text © S. A. Eremeyev, V. I. Kargin, K. A. Motovilov, V. N. Tashlitsky, V. Yu. Markov, G. A. Korshunova, N. V. Sumbatyan, M. Yu. Vyssokikh, L. S. Yaguzhinsky, 2009, published in Biokhimiya, 2009, Vol. 74, No. 10, pp. 1368–1379.

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Eremeyev, S.A., Kargin, V.I., Motovilov, K.A. et al. Molecular mechanisms of transformation of SkQ mitotropic quinones and the search for new approaches to creation of selective free radical traps. Biochemistry Moscow 74, 1114–1124 (2009). https://doi.org/10.1134/S0006297909100071

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Key words

  • free radical traps
  • mitochondria
  • ROS
  • SkQ
  • MitoQ
  • uncoupling