Biochemistry (Moscow)

, Volume 70, Issue 2, pp 222–230 | Cite as

Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology

  • M. F. Ross
  • G. F. Kelso
  • F. H. Blaikie
  • A. M. James
  • H. M. Cochemé
  • A. Filipovska
  • T. Da Ros
  • T. R. Hurd
  • R. A. J. Smith
  • M. P. MurphyEmail author


Lipophilic phosphonium cations were first used to investigate mitochondrial biology by Vladimir Skulachev and colleagues in the late 1960s. Since then, these molecules have become important tools for exploring mitochondrial bioenergetics and free radical biology. Here we review why these molecules are useful in mitochondrial research and outline some of the ways in which they are now being utilized.

Key words

lipophilic phosphonium cations mitochondria membrane potential oxidative damage antioxidants 



dielectric constant




glutathione disulfide


tetraphenylphosphonium cation


(4-iodobutyl)triphenylphosphonium cation


membrane potential




(4-thiobutyl)triphenylphosphonium cation


tetraphenylborate anion


methyltriphenylphosphonium cation


triphenylphosphonium cation


reduced thioredoxin


oxidized thioredoxin


Born energy


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  1. 1.
    Nicholls, D. G., and Ferguson, S. J. (2002) Bioenergetics 3, Academic Press, London.Google Scholar
  2. 2.
    Liberman, E. A., Topali, V. P., Tsofina, L. M., Jasaitis, A. A., and Skulachev, V. P. (1969) Nature, 222, 1076–1078.PubMedGoogle Scholar
  3. 3.
    Liberman, E. A., and Topaly, V. P. (1969) Biofizika, 14, 452–461.PubMedGoogle Scholar
  4. 4.
    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, 13–21.PubMedGoogle Scholar
  5. 5.
    Grinius, L. L., Jasaitis, A. A., Kadziauskas, Y. P., Liberman, E. A., Skulachev, V. P., Topali, V. P., Tsofina, L. M., and Vladimirova, M. A. (1970) Biochim. Biophys. Acta, 216, 1–12.PubMedGoogle Scholar
  6. 6.
    Lewis, M. R., and Lewis, W. H. (1915) Am. J. Anat., 17, 339–401.Google Scholar
  7. 7.
    Ketterer, B., Neumcke, B., and Laeuger, P. (1971) J. Membr. Biol., 5, 225–245.Google Scholar
  8. 8.
    Murphy, M. P. (1997) Trends Biotechnol., 15, 326–330.PubMedGoogle Scholar
  9. 9.
    Flewelling, R. F., and Hubbell, W. L. (1986) Biophys. J., 49, 531–540.PubMedGoogle Scholar
  10. 10.
    Honig, B. H., Hubbell, W. L., and Flewelling, R. F. (1986) Annu. Rev. Biophys. Biophys. Chem., 15, 163–193.PubMedGoogle Scholar
  11. 11.
    Gennis, R. B. (1989) in Biomembranes:Molecular Structure and Function, Springer, New York, pp. 235–269.Google Scholar
  12. 12.
    Grunwald, E., Baughman, G., and Kohnstam, G. (1960) JACS, 82, 5801–5811.Google Scholar
  13. 13.
    Flewelling, R. F., and Hubbell, W. L. (1986) Biophys. J., 49, 541–552.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith, R. A., Kelso, G. F., James, A. M., and Murphy, M. P. (2004) Meth. Enzymol., 382, 45–67.PubMedGoogle Scholar
  15. 15.
    Cafiso, D. S., and Hubbell, W. L. (1981) Annu. Rev. Biophys. Bioeng., 10, 217–244.PubMedGoogle Scholar
  16. 16.
    Ono, A., Miyauchi, S., Demura, M., Asakura, T., and Kamo, N. (1994) Biochemistry, 33, 4312–4318.PubMedGoogle Scholar
  17. 17.
    Brand, M. D. (1995) in Bioenergetics — a Practical Approach (Brown, G. C., and Cooper, C. E., eds.) IRL, Oxford, pp. 39–62.Google Scholar
  18. 18.
    Azzone, G. F., Pietrobon, D., and Zoratti, M. (1984) Curr. Top. Bioenerg., 13, 1–77.Google Scholar
  19. 19.
    McLaughlin, S., and Harary, H. (1976) Biochemistry, 15, 1941–1948.PubMedGoogle Scholar
  20. 20.
    Demura, M., Kamo, N., and Kobatake, Y. (1985) Biochim. Biophys. Acta, 820, 207–215.Google Scholar
  21. 21.
    Rottenberg, H. (1984) J. Membr. Biol., 81, 127–138.PubMedGoogle Scholar
  22. 22.
    Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A. J., and Murphy, M. P. (2001) J. Biol. Chem., 276, 4588–4596.PubMedGoogle Scholar
  23. 23.
    Asin Cayuela, J., Manas, A. R., James, A. M., Smith, R. A., and Murphy, M. P. (2004) FEBS Lett., 571, 9–16.PubMedGoogle Scholar
  24. 24.
    Brown, G. C., and Brand, M. D. (1985) Biochem. J., 225, 399–405.PubMedGoogle Scholar
  25. 25.
    Rottenberg, H. (1979) Meth. Enzymol., 55, 547–569.CrossRefPubMedGoogle Scholar
  26. 26.
    Kamo, N., Muratsugu, M., Hongoh, R., and Kobatake, Y. (1979) J. Membr. Biol., 49, 105–121.PubMedGoogle Scholar
  27. 27.
    Brand, M. D., and Felber, S. M. (1984) Biochem. J., 217, 453–459.PubMedGoogle Scholar
  28. 28.
    Nobes, C. D., Brown, G. C., Olive, P. N., and Brand, M. D. (1990) J. Biol. Chem., 265, 12903–12909.PubMedGoogle Scholar
  29. 29.
    Scarlett, J. L., Sheard, P. W., Hughes, G., Ledgerwood, E. C., Ku, H. H., and Murphy, M. P. (2000) FEBS Lett., 475, 267–272.PubMedGoogle Scholar
  30. 30.
    Kauppinen, R. (1983) Biochim. Biophys. Acta, 725, 131–137.PubMedGoogle Scholar
  31. 31.
    Wan, B., Doumen, C., Duszynski, J., Salama, G., and LaNoue, K. F. (1993) Am. J. Physiol., 265, H445–H452.PubMedGoogle Scholar
  32. 32.
    Steen, H., Maring, J. G., and Meijer, D. K. (1993) Biochem. Pharmacol., 45, 809–818.PubMedGoogle Scholar
  33. 33.
    Rolfe, D. F. S., and Brand, M. D. (1996) Biochim. Biophys. Acta, 1276, 45–50.PubMedGoogle Scholar
  34. 34.
    Weissig, V., and Torchilin, V. P. (2001) Adv. Drug Deliv. Rev., 49, 1–2.PubMedGoogle Scholar
  35. 35.
    Murphy, M. P., and Smith, R. A. J. (2000) Adv. Drug Deliv. Rev., 41, 235–250.PubMedGoogle Scholar
  36. 36.
    Green, K., Brand, M. D., and Murphy, M. P. (2004) Diabetes, 53(Suppl. 1), S110–118.PubMedGoogle Scholar
  37. 37.
    Chen, L. B. (1988) Annu. Rev. Cell Biol., 4, 155–181.PubMedGoogle Scholar
  38. 38.
    Smith, R. A. J., Porteous, C. M., Coulter, C. V., and Murphy, M. P. (1999) Eur. J. Biochem., 263, 709–716.PubMedGoogle Scholar
  39. 39.
    Murphy, M. P., Echtay, K. S., Blaikie, F. H., Asin Cayuela, J., Cocheme, H. M., Green, K., Buckingham, J. A., Taylor, E. R., Hurrell, F., Hughes, G., Miwa, S., Cooper, C. E., Svistunenko, D. A., Smith, R. A., and Brand, M. D. (2003) J. Biol. Chem., 278, 48534–48545.PubMedGoogle Scholar
  40. 40.
    James, A. M., Blaikie, F. H., Smith, R. A., Lightowlers, R. N., Smith, P. M., and Murphy, M. P. (2003) Eur. J. Biochem., 270, 2827–2836.PubMedGoogle Scholar
  41. 41.
    Raha, S., and Robinson, B. H. (2000) Trends Biochem. Sci., 25, 502–508.PubMedGoogle Scholar
  42. 42.
    Beckman, K. B., and Ames, B. N. (1998) Physiol. Rev., 78, 547–581.PubMedGoogle Scholar
  43. 43.
    Wallace, D. C. (1999) Science, 283, 1482–1488.PubMedGoogle Scholar
  44. 44.
    Finkel, T. (1998) Curr. Opin. Cell Biol., 10, 248–253.PubMedGoogle Scholar
  45. 45.
    Finkel, T., and Holbrook, N. J. (2000) Nature, 408, 239–247.PubMedGoogle Scholar
  46. 46.
    Murphy, M. P. (2001) Exp. Opin. Biol. Ther., 1, 753–764.Google Scholar
  47. 47.
    Jauslin, M. L., Meier, T., Smith, R. A. J., and Murphy, M. P. (2003) FASEB J., 17, 1972–1974.PubMedGoogle Scholar
  48. 48.
    Dhanasekaran, A., Kotamraju, S., Kalivendi, S. V., Matsunaga, T., Shang, T., Keszler, A., Joseph, J., and Kalyanaraman, B. (2004) J. Biol. Chem., 279, 37575–37587.PubMedGoogle Scholar
  49. 49.
    Campuzano, V., Montermini, L., Molto, M. D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., et al. (1996) Science, 271, 1423–1427.PubMedGoogle Scholar
  50. 50.
    Kaplan, J. (1999) Proc. Natl. Acad. Sci. USA, 96, 10948–10949.PubMedGoogle Scholar
  51. 51.
    Smith, R. A. J., Porteous, C. M., Gane, A. M., and Murphy, M. P. (2003) Proc. Natl. Acad. Sci. USA, 100, 5407–5412.PubMedGoogle Scholar
  52. 52.
    Hwang, P. M., Bunz, F., Yu, J., Rago, C., Chan, T. A., Murphy, M. P., Kelso, G. F., Smith, R. A. J., Kinzler, K. W., and Vogelstein, B. (2001) Nat. Med., 7, 1111–1117.PubMedGoogle Scholar
  53. 53.
    Saretzki, G., Murphy, M. P., and von Zglinicki, T. (2003) Aging Cell, 2, 141–143.PubMedGoogle Scholar
  54. 54.
    Echtay, K. S., Murphy, M. P., Smith, R. A., Talbot, D. A., and Brand, M. D. (2002) J. Biol. Chem., 277, 47129–47135.PubMedGoogle Scholar
  55. 55.
    Weiss, M. J., Wong, J. R., Ha, C. S., Bleday, R., Salem, R. R., Steele, G. D., Jr., and Chen, L. B. (1987) Proc. Natl. Acad. Sci. USA, 84, 5444–5448.PubMedGoogle Scholar
  56. 56.
    Rideout, D. C., Calogeropoulou, T., Jaworski, J. S., Dagnino, R., and McCarthy, M. R. (1989) Anti Cancer Drug Design., 4, 265–280.PubMedGoogle Scholar
  57. 57.
    Modica Napolitano, J. S., and Singh, K. (2002) Expert Rev. Mol. Med., 2002, 1–19.Google Scholar
  58. 58.
    Modica Napolitano, J. S., and Aprille, J. R. (2001) Adv. Drug Deliv. Rev., 49, 63–70.PubMedGoogle Scholar
  59. 59.
    Manetta, A., Gamboa, G., Nasseri, A., Podnos, Y. D., Ema, D., Dorion, G., Rawlings, L., Carpenter, P. M., Bustamante, A., Patel, J., and Rideout, D. (1996) Gynecol. Oncol., 60, 203–212.PubMedGoogle Scholar
  60. 60.
    Patel, J., Rideout, D., McCarthy, M. R., Calogeropoulou, T., Wadwa, K. S., and Oseroff, A. R. (1994) Anticancer Res., 14, 21–28.PubMedGoogle Scholar
  61. 61.
    Rideout, D., Bustamante, A., and Patel, J. (1994) Int. J. Cancer, 57, 247–253.PubMedGoogle Scholar
  62. 62.
    Rideout, D. (1994) Cancer Invest., 12, 189–202.PubMedGoogle Scholar
  63. 63.
    Costa, N. J., Dahm, C. C., Hurrell, F., Taylor, E. R., and Murphy, M. P. (2003) Antiox. Redox Signal, 5, 291–305.Google Scholar
  64. 64.
    Beer, S. M., Taylor, E. R., Brown, S. E., Dahm, C. C., Costa, N. J., Runswick, M. J., and Murphy, M. P. (2004) J. Biol. Chem., [Aug 30; epub ahead of print ].Google Scholar
  65. 65.
    Lin, T. K., Hughes, G., Muratovska, A., Blaikie, F. H., Brookes, P. S., Darley Usmar, V., Smith, R. A. J., and Murphy, M. P. (2002) J. Biol. Chem., 277, 17048–17056.PubMedGoogle Scholar
  66. 66.
    Burns, R. J., and Murphy, M. P. (1997) Arch. Biochem. Biophys., 339, 33–39.PubMedGoogle Scholar
  67. 67.
    Burns, R. J., Smith, R. A. J., and Murphy, M. P. (1995) Arch. Biochem. Biophys., 322, 60–68.PubMedGoogle Scholar
  68. 68.
    Taylor, E. R., Hurrell, F., Shannon, R. J., Lin, T. K., Hirst, J., and Murphy, M. P. (2003) J. Biol. Chem., 278, 19603–19610.PubMedGoogle Scholar
  69. 69.
    Venkatraman, A., Landar, A., Davis, A. J., Ulasova, E., Page, G., Murphy, M. P., Darley Usmar, V., and Bailey, S. M. (2004) Am. J. Physiol. Gastrointest. Liver Physiol., 286, G521–527.PubMedGoogle Scholar
  70. 70.
    Filipovska, A., Eccles, M. R., Smith, R. A., and Murphy, M. P. (2004) FEBS Lett., 556, 180–186.PubMedGoogle Scholar

Copyright information

© MAIK “Nauka/Interperiodica” 2005

Authors and Affiliations

  • M. F. Ross
    • 1
  • G. F. Kelso
    • 2
  • F. H. Blaikie
    • 2
  • A. M. James
    • 1
  • H. M. Cochemé
    • 1
  • A. Filipovska
    • 1
  • T. Da Ros
    • 3
  • T. R. Hurd
    • 1
  • R. A. J. Smith
    • 2
  • M. P. Murphy
    • 1
    Email author
  1. 1.MRC Dunn Human Nutrition UnitCambridgeUK
  2. 2.Department of ChemistryUniversity of OtagoDunedinNew Zealand
  3. 3.Pharmaceutical Science DepartmentTrieste UniversityTriesteItaly

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