Biochemistry (Moscow)

, Volume 72, Issue 12, pp 1385–1396 | Cite as

A biochemical approach to the problem of aging: “Megaproject” on membrane-penetrating ions. The first results and prospects

Review

Abstract

Antioxidants specifically addressed to mitochondria have been studied for their ability to decelerate aging of organisms. For this purpose, a project has been established with participation of several research groups from Belozersky Institute of Physico-Chemical Biology and some other Russian research institutes as well as two groups from the USA and Sweden, with support by the “Mitotechnology” company founded by “RAInKo” company (O. V. Deripaska and Moscow State University). This paper summarizes the first results of the project and estimates its prospects. Within the framework of the project, antioxidants of a new type (SkQ) were synthesized comprising plastoquinone (an antioxidant moiety), a penetrating cation, and decane or pentane linker. Using planar bilayer phospholipid membranes, we selected SkQ derivatives with the highest penetrating ability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decylrhodamine 19 (SkQR1), and methylplastoquinonyl-decyl-triphenylphosphonium (SkQ3). Anti-and prooxidant properties of these substances and also of ubiquinone and ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested on isolated mitochondria. Micromolar concentrations of cationic quinones are found to be very strong prooxidants, but in lower (submicromolar) concentrations they display antioxidant activity. The antioxidant activity decreases in the series SkQ1 = SkQR1 > SkQ3 > MitoQ, so the window between the anti-and prooxidant effects is smallest for MitoQ. SkQ1 is rapidly reduced by complexes I and II of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Extremely low concentrations of SkQ1 and SkQR1 completely arrest the H2O2-induced apoptosis in human fibroblasts and HeLa cells (for SkQ1 C1/2 = 1·10−9 M) Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In mice, SkQ1 decelerates the development of three types of accelerated aging (progeria) and also of normal aging, and this effect is especially demonstrative at early stages of aging. The same pattern is shown in invertebrates (drosophila and daphnia). In mammals, the effect of SkQs on aging is accompanied by inhibition of development of such age-related diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. SkQ1 manifests a strong therapeutic action on some already developed retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM skQ1, vision is recovered in 50 of 66 animals who became blind because of retinopathy. SkQ1-containing drops instilled in the early stage of the disease prevent the loss of sight in rabbits with experimental uveitis and restore vision to animals that had already become blind. A favorable effect is also achieved in experimental glaucoma in rabbits. Moreover, the pretreatment of rats with 0.2 nmol SkQ1 per kg body weight significantly decreases the H2O2-induced arrhythmia of the isolated heart. SkQ1 strongly reduces the damaged area in myocardial infarction or stroke and prevents the death of animals from kidney infarction. In p53−/− mice, SkQ1 decreases the ROS level in the spleen cells and inhibits appearance of lymphomas which are the main cause of death of such animals. Thus, it seems reasonable to perform clinical testing of SkQ preparations as promising drugs for treatment of age-related and some other severe diseases of human and animals.

Key words

aging mitochondria reactive oxygen species SkQs antioxidants 

Abbreviations

Δψ

transmembrane electric potential

BLM

planar bilayer phospholipid membrane

C12TPP

dodecyl triphenylphosphonium

DMQ

demethoxyMitoQ

MitoQ

compound of ubiquinone and decyl triphenylphosphonium

ROS

reactive oxygen species

SkQ

compounds of plastoquinone or methylplastoquinone and decyl (or amyl) triphenylphosphonium, methylcarninite, or tributylammonium

SkQ1

compound of plastoquinone and decyl triphenylphosphonium (other SkQ derivatives are shown in Fig. 3)

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Skulachev, V. P. (1999) Biochemistry (Moscow), 64, 1418–1426.Google Scholar
  2. 2.
    Skulachev, V. P. (2003) in Topics in Current Genetics. Model Systems in Ageing (Nystrom, T., and Osiewacz, H. D., eds.) Vol. 3, Springer-Verlag, Berlin-Heidelberg, pp. 191–238.Google Scholar
  3. 3.
    Lewis, K. (2000) Microbiol. Mol. Biol. Rev., 64, 503–514.PubMedCrossRefGoogle Scholar
  4. 4.
    Longo, V. D., Mitteldorf, J., and Skulachev, V. P. (2005) Nature Rev. Genet., 6, 866–872.CrossRefPubMedGoogle Scholar
  5. 5.
    Skulachev, V. P. (2005) Vestn. Ros. Akad. Nauk, 75, 831–843.Google Scholar
  6. 6.
    Skulachev, V. P., and Longo, V. D. (2005) Ann. N. Y. Acad. Sci., 1057, 145–164.PubMedCrossRefGoogle Scholar
  7. 7.
    Darwin, Ch. (1871) The Descent of Man, Murray, London.Google Scholar
  8. 8.
    Weissmann, A. (1889) Essays upon Heredity and Kindred Biological Problems, Claderon Press, Oxford.Google Scholar
  9. 9.
    Harman, D. (1956) J. Gerontol., 11, 298–300.PubMedGoogle Scholar
  10. 10.
    Skulachev, V. P. (1999) Mol. Asp. Med., 20, 139–184.CrossRefGoogle Scholar
  11. 11.
    Grivennikova, V. G., and Vinogradov, A. D. (2006) Biochim. Biophys. Acta, 1757, 553–561.PubMedCrossRefGoogle Scholar
  12. 12.
    Lambert, A. J., Boysen, H. M., Buckingham, J. A., Yang, T., Podlutsky, A., Austad, S. N., Kunz, T. H., Buffenstein, R., and Brand, M. D. (2007) Aging Cell, 6, 607–618.PubMedCrossRefGoogle Scholar
  13. 13.
    Buffenstein, R. (2005) J. Gerontol. Biol. Sci., 60, 1369–1377.Google Scholar
  14. 14.
    Andziak, B., and Buffenstein, R. (2006) Aging Cell, 5, 525–532.PubMedCrossRefGoogle Scholar
  15. 15.
    Andziak, B., O’Connor, T. P., Qi, W., DeWaal, E. M., Pierce, A., Chaudhuri, A. R., van Remmen, H., and Buffenstein, R. (2006) Aging Cell, 5, 463–471.PubMedCrossRefGoogle Scholar
  16. 16.
    Andziak, B., O’Connor, T. P., and Buffenstein, R. (2005) Mech. Ageing Dev., 126, 1206–1212.PubMedCrossRefGoogle Scholar
  17. 17.
    Labinsky, N., Csiszar, A., Orosz, Z., Smith, K., Rivera, A., Buffenstein, R., and Ungvari, Z. (2006) Am. J. Physiol. Heart Circ. Physiol., 291, H2698–H2704.CrossRefGoogle Scholar
  18. 18.
    Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Revoldi, P., Pandolfi, P. P., Lanfrancone, L., and Pelicci, P. G. (1999) Nature, 402, 309–313.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu, X., Jiang, N., Hughes, B., Bigras, E., Shoubridge, E., and Hekimi, S. (2006) Gen. Dev., 19, 2424–2434.CrossRefGoogle Scholar
  20. 20.
    Chu, H.-P., Grigorian, I. A., Dorovkov, M. V., Nagele, R. G., Komarova, E. A., Gudkov, A. V., Harrison, D. E., and Ryazanov, A. G. (2007) Nature, in press.Google Scholar
  21. 21.
    Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., Bartholomew, J. C., and Ames, B. N. (2002) Proc. Natl. Acad. Sci. USA, 99, 1870–1875.PubMedCrossRefGoogle Scholar
  22. 22.
    Atamna, H., Robinson, C., Ingersoll, R., Elliott, H., and Ames, B. N. (2001) FASEB J., 15, 196–204.CrossRefGoogle Scholar
  23. 23.
    Howes, R. M. (2006) Ann. N. Y. Acad. Sci., 1067, 22–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Goldstein, N. (2002) Biochemistry (Moscow), 67, 161–170.CrossRefGoogle Scholar
  25. 25.
    Liberman, E. A., Topali, V. P., Tsofina, L. M., Jasaitis, A. A., and Skulachev, V. P. (1969) Nature, 222, 1076–1078.PubMedCrossRefGoogle Scholar
  26. 26.
    Grinius, L. L., Jasaitis, A. A., Kadziauskas, Yu. L., Liberman, E. A., Skulachev, V. P., Topali, V. P., Tsofina, L. M., and Vladimirova, M. A. (1970) Biochim. Biophys. Acta, 216, 1–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Bakeeva, L. E., Grinius, L. L., Jasaitis, A. A., Kuliene, V. V., Levitsky, D. O., Liberman, E. A., Severina, I. I., and Skulachev, V. P. (1970) Biochim. Biophys. Acta, 216, 12–21.Google Scholar
  28. 28.
    Liberman, E. A., and Skulachev, V. P. (1970) Biochim. Biophys. Acta, 216, 30–42.PubMedCrossRefGoogle Scholar
  29. 29.
    Skulachev, V. P. (1989) Membrane Bioenergetics, Springer Verlag, Berlin.Google Scholar
  30. 30.
    Severin, S. E., Skulachev, V. P., and Yaguzinsky, L. S. (1970) Biokhimiya, 35, 1250–1257.Google Scholar
  31. 31.
    Smith, R. A., Porteous, C. M., Coulter, C. V., and Murphy, M. P. (1999) Eur. J. Biochem., 263, 709–716.PubMedCrossRefGoogle Scholar
  32. 32.
    Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A., and Murphy, M. P. (2001) J. Biol. Chem., 276, 4588–4596.PubMedCrossRefGoogle Scholar
  33. 33.
    Murphy, M. P., and Smith, R. A. (2007) Annu. Rev. Pharmacol. Toxicol., 47, 629–656.PubMedCrossRefGoogle Scholar
  34. 34.
    James, A. M., Cocheme, H. M., Smith, R. A., and Murphy, M. P. (2005) J. Biol. Chem., 280, 21295–21312.PubMedCrossRefGoogle Scholar
  35. 35.
    Kelso, G. F., Porteous, C. M., Hughes, G., Ledgerwood, E. C., Gane, A. M., Smith, R. A., and Murphy, M. P. (2002) Ann. N. Y. Acad. Sci., 959, 263–274.PubMedCrossRefGoogle Scholar
  36. 36.
    Saretzki, G., Murphy, M. P., and von Zglinicki, T. (2003) Aging Cell, 2, 141–143.PubMedCrossRefGoogle Scholar
  37. 37.
    Jauslin, M. L., Meier, T., Smith, R. A., and Murphy, M. P. (2003) FASEB J., 17, 1972–1974.PubMedGoogle Scholar
  38. 38.
    Antonenko, Yu. N., Archipova, L. T., Archipova, M. M., Bakeeva, L. E., Chernyak, B. F., Domnina, L. V., Fursova, A. Zh., Grigorian, E. N., Ivanova, O. Yu., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Kolosova, N. G., Kopenkin, E. P., Korshunov, S. S., Korshunova, G. A., Kovaleva, N. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Philippov, P. P., Pletjushkina, O. Yu., Pustovidko, A. V., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Senin, I. I., Severina, I. I., Simonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sotnikova, L. F., Sumbatyan, N. V., Tashlitsky, V. N., Trofimova, N. A., Vassiliev, Yu. M., Vyssokikh, M. Yu., Yaguzhinsky, L. S., and Skulachev, V. P. (2007), in press.Google Scholar
  39. 39.
    Lakowski, B., and Hekimi, S. (1996) Science, 272, 1010–1013.PubMedCrossRefGoogle Scholar
  40. 40.
    Kruk, J., Jemiola-Rzeminska, M., and Strzalka, K. (1997) Chem. Phys. Lipids, 87, 73–80.CrossRefGoogle Scholar
  41. 41.
    Roginsky, V., Barsukova, T., Loshadkin, D., and Pliss, E. (2003) Chem. Phys. Lipids, 125, 49–58.PubMedCrossRefGoogle Scholar
  42. 42.
    Skulachev, V. P., Bakeeva, L. E., Chernyak, B. V., Domnina, L. V., Minin, A. A., Pletjushkina, O. Yu., Saprunova, V. B., Skulachev, I. V., Tsyplenkova, V. G., Vasiliev, J. M., Yaguzhinsky, L. S., and Zorov, D. B. (2004) Mol. Cell. Biochem., 256/257, 341–358.CrossRefGoogle Scholar
  43. 43.
    Skulachev, V. P., et al., in preparation.Google Scholar
  44. 44.
    Trifunovic, A., Wreeenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly, Y. M., Gidlof, S., Oldfors, A., Wilbom, R., Tornell, J., Jacobs, H. T., and Larsson, N.-G. (2004) Nature, 429, 417–423.PubMedCrossRefGoogle Scholar
  45. 45.
    Solov’eva, N. A., Morozkova, T. S., and Salganik, R. I. (1975) Genetika, 11, 63–71.PubMedGoogle Scholar
  46. 46.
    Kolosova, N. G., Lebedev, P. A., Aidagulova, S. V., and Morozkova, T. S. (2003) Bull. Exp. Biol. Med., 136, 415–419.PubMedCrossRefGoogle Scholar
  47. 47.
    Sergeeva, S., Bagryanskaya, E., Korbolina, E., and Kolosova, N. (2006) Exp. Gerontol., 41, 141–150.PubMedCrossRefGoogle Scholar
  48. 48.
    Kolosova, N. G., Shcheglova, T. V., Sergeeva, S. V., and Loskutova, L. V. (2006) Neurobiol. Aging, 27, 1289–1297.PubMedCrossRefGoogle Scholar
  49. 49.
    Vlachantoni, D., Tulloch, B., Taylor, R. W., Turnbull, D. M., Murphy, M. P., and Wright, A. F. (2006) Invest. Ophthalmol. Vis. Sci., E-5773.Google Scholar
  50. 50.
    Rajendram, R., Saraswathy, S., and Rao, N. A. (2007) Br. J. Ophthalmol., 91, 531–537.PubMedCrossRefGoogle Scholar
  51. 51.
    Moreno, M. C., Campanelli, J., Sande, P., Sanez, D. A., Keller Sarmiento, M. I., and Rosenstein, R. E. (2004) Free Rad. Biol. Med., 37, 803–812.PubMedCrossRefGoogle Scholar
  52. 52.
    Madeo, F., Frohlich, E., Ligr, M., Grey, M., Sigrist, S. J., Wolf, D. H., and Frohlich, K.-U. (1999) J. Cell Biol., 145, 757–767.PubMedCrossRefGoogle Scholar
  53. 53.
    Anisimov, V. N., Semenchenko, A. V., and Yashin, A. I. (2003) Biogerontology, 4, 297–307.PubMedCrossRefGoogle Scholar
  54. 54.
    Hamilton, W. D. (1964) J. Theor. Biol., 7, 1–16, 17–52.PubMedCrossRefGoogle Scholar
  55. 55.
    Dowkins, R. (1976) The Selfish Gene, Oxford University Publishers, Oxford.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2007

Authors and Affiliations

  1. 1.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
  2. 2.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia

Personalised recommendations