Skip to main content
SpringerLink
Log in

Uncoupling and toxic action of alkyltriphenylphosphonium cations on mitochondria and the bacterium Bacillus subtilis as a function of alkyl chain length

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

A series of permeating cations based on alkyl derivatives of triphenylphosphonium (Cn-TPP+) containing linear hydrocarbon chains (butyl, octyl, decyl, and dodecyl) was investigated in systems of isolated mitochondria, bacteria, and liposomes. In contrast to some derivatives (esters) of rhodamine-19, wherein butyl rhodamine possessed the maximum activity, in the case of Cn-TPP a stimulatory effect on mitochondrial respiration steadily increased with growing length of the alkyl radical. Tetraphenylphosphonium and butyl-TPP+ at a dose of several hundred micromoles exhibited an uncoupling effect, which might be related to interaction between Cn-TPP+ and endogenous fatty acids and induction of their own cyclic transfer, resulting in transport of protons across the mitochondrial membrane. Such a mechanism was investigated by measuring efflux of carboxyfluorescein from liposomes influenced by Cn-TPP+. Experiments with bacteria demonstrated that dodecyl-TPP+, decyl-TPP+, and octyl-TPP+ similarly to quinone-containing analog (SkQ1) inhibited growth of the Gram-positive bacterium Bacillus subtilis, wherein the inhibitory effect was upregulated with growing lipophilicity. These cations did not display toxic effect on growth of the Gram-negative bacterium Escherichia coli. It is assumed that the difference in toxic action on various bacterial species might be related to different permeability of bacterial coats for the examined triphenylphosphonium cations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CF:

5(6)-carboxyfluorescein

Cn-TPP+ :

alkyl-triphenylphosphonium cation

DiS-C3-(5):

potential-dependent carbocyanine probe

ΔμH+ :

mitochondrial transmembrane proton electrochemical gradient

ΔpH:

pH gradient across the inner membrane of mitochondria

Δψ:

mitochondrial membrane potential

FCCP:

arbonyl cyanide p-trifluoromethoxyphenylhydrazone

Phe4P+ :

tetraphenylphosphonium cation

SkQ1:

10-(plastoquinonyl)decyltriphenylphosphonium

References

  1. Skulachev, V. P., Antonenko, Y. N., Cherepanov, D. A., Chernyak, B. V., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Pletjushkina, O. Y., Roginsky, V. A., Rokitskaya, T. I., Severin, F. F., Severina, I. I., Simonyan, R. A., Skulachev, M. V., Sumbatyan, N. V., Sukhanova, E. I., Tashlitsky, V. N., Trendeleva, T. A., Vyssokikh, M. Y., and Zvyagilskaya, R. A. (2010. Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs), Biochim. Biophys. Acta, 1797, 878–889.

    Article  CAS  PubMed  Google Scholar 

  2. Murphy, M. P., and Smith, R. A. (2007. Targeting antioxidants to mitochondria by conjugation to lipophilic cations, Annu. Rev. Pharmacol. Toxicol., 47, 629–656.

    Article  CAS  PubMed  Google Scholar 

  3. Cunha, F. M., Caldeira da Silva, C. C., Cerqueira, F. M., and Kowaltowski, A. J. (2011. Mild mitochondrial uncoupling as a therapeutic strategy, Curr. Drug Targets, 12, 783–789.

    Article  CAS  PubMed  Google Scholar 

  4. Korshunov, S. S., Skulachev, V. P., and Starkov, A. A. (1997. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria, FEBS Lett., 416, 15–18.

    Article  CAS  PubMed  Google Scholar 

  5. Severin, F. F., Severina, I. I., Antonenko, Y. N., Rokitskaya, T. I., Cherepanov, D. A., Mokhova, E. N., Vyssokikh, M. Y., Pustovidko, A. V., Markova, O. V., Yaguzhinsky, L. S., Korshunova, G. A., Sumbatyan, N. V., Skulachev, M. V., and Skulachev, V. P. (2010. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore, Proc. Natl. Acad. Sci. USA, 107, 663–668.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies, Biochemistry (Moscow), 73, 12731287.

    Article  Google Scholar 

  7. Khailova, L. S., Silachev, D. N., Rokitskaya, T. I., Avetisyan, A. V., Lyamsaev, K. G., Severina, I. I., Il’yasova, T. M., Gulyaev, M. V., Dedukhova, V. I., Trendeleva, T. A., Plotnikov, E. Y., Zvyagilskaya, R. A., Chernyak, B. V., Zorov, D. B., Antonenko, Y. N., and Skulachev, V. P. (2014. A short-chain alkyl derivative of rhodamine 19 acts as a mild uncoupler of mitochondria and a neuroprotector, Biochim. Biophys. Acta, 1837, 1739–1747.

    Article  CAS  PubMed  Google Scholar 

  8. Sassi, N., Mattarei, A., Azzolini, M., Szabo’, I., Paradisi, C., Zoratti, M., and Biasutto, L. (2014. Cytotoxicity of mitochondria-targeted resveratrol derivatives: interactions with respiratory chain complexes and ATP synthase, Biochim. Biophys. Acta, 1837, 1781–1789.

    Article  CAS  PubMed  Google Scholar 

  9. Severina, I. I., Muntyan, M. S., Lewis, K., and Skulachev, V. P. (2001. Transfer of cationic antibacterial agents berberine, palmatine, and benzalkonium through bimolecular planar phospholipid film and Staphylococcus aureus membrane, IUBMB Life, 52, 321–324.

    Article  CAS  PubMed  Google Scholar 

  10. Schmeller, T., Latz-Bruning, B., and Wink, M. (1997. Biochemical activities of berberine, palmatine, and sanguinarine mediating chemical defence against microorganisms and herbivores, Phytochemistry, 44, 257–266.

    Article  CAS  PubMed  Google Scholar 

  11. Galkina, I. V., and Egorova, S. N. (2009. Biological activity of quaternary salts of phosphonium and perspectives of their medical application, Farmatsiya, 9, 142–145.

    Google Scholar 

  12. Galkina, I. V., Bakhtiyarova, Y. V., Shulaeva, M. P., Pozdeev, O. K., Egorova, S. N., Cherkasov, R. A., and Galkin, V. I. (2013) Synthesis and antimicrobial activity of carboxylate phosphabetaines derivatives with alkyl chains of various lengths, J. Chem., doi: 10.1155/2013/302937.

    Google Scholar 

  13. Kanazawa, A., Ikeda, T., and Endo, T. (1994. Synthesis and antimicrobial activity of dimethyl-substituted and trimethylsubstituted phosphonium salts with alkyl chains of various lengths, Antimicrob. Agents Chemother., 38, 945–952.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ross, M. F., Prime, T. A., Abakumova, I., James, A. M., Porteous, C. M., Smith, R. A., and Murphy, M. P. (2008. Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochem. J., 411, 633–645.

    Article  CAS  PubMed  Google Scholar 

  15. Rokitskaya, T. I., Sumbatyan, N. V., Tashlitsky, V. N., Korshunova, G. A., Antonenko, Y. N., and Skulachev, V. P. (2010. Mitochondria-targeted penetrating cations as carriers of hydrophobic anions through lipid membranes, Biochim. Biophys. Acta, 1798, 1698–1706.

    Article  CAS  PubMed  Google Scholar 

  16. Johnson, D., and Lardy, H. (1967. Isolation of liver or kidney mitochondria, Methods Enzymol., 10, 94–96.

    Article  CAS  Google Scholar 

  17. Akerman, K. E., and Wikstrom, M. K. (1976. Safranine as a probe of the mitochondrial membrane potential, FEBS Lett., 68, 191–197.

    Article  CAS  PubMed  Google Scholar 

  18. Miller, J. B., and Koshland, D. E., Jr. (1977. Sensory electrophysiology of bacteria: relationship of the membrane potential to motility and chemotaxis in Bacillus subtilis, Proc. Natl. Acad. Sci. USA, 74, 4752–4756.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Trendeleva, T. A., Rogov, A. G., Cherepanov, D. A., Sukhanova, E. I., Il’yasova, T. M., Severina, I. I., and Zvyagilskaya, R. A. (2012. Interaction of tetraphenylphosphonium and dodecyltriphenylphosphonium with lipid membranes and mitochondria, Biochemistry (Moscow), 77, 1021–1028.

    Article  CAS  Google Scholar 

  20. Lotscher, H. R., Winterhalter, K. H., Carafoli, E., and Richter, C. (1980. The energy state of mitochondria during the transport of Ca2+, Eur. J. Biochem., 110, 211–216.

    Article  CAS  PubMed  Google Scholar 

  21. Kramer, R., and Palmieri, F. (1989. Molecular aspects of isolated and reconstituted carrier proteins from animal mitochondria, Biochim. Biophys. Acta, 974, 1–23.

    Article  CAS  PubMed  Google Scholar 

  22. Yang, Q., Liu, X. Y., Umetani, K., Kamo, N., and Miyake, J. (1999. Partitioning of triphenylalkylphosphonium homologues in gel bead-immobilized liposomes: chromatographic measurement of their membrane partition coefficients, Biochim. Biophys. Acta, 1417, 122–130.

    Article  CAS  PubMed  Google Scholar 

  23. 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. Conversion of biomembrane-produced energy into electric form. II. Intact mitochondria, Biochim. Biophys Acta, 216, 13–21.

    Article  CAS  PubMed  Google Scholar 

  24. Thorsteinsson, T., Loftsson, T., and Masson, M. (2003. Soft antibacterial agents, Curr. Med. Chem., 10, 1129–1136.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, 119991, Moscow, Russia

    L. S. Khailova, P. A. Nazarov, G. A. Korshunova, T. I. Rokitskaya, V. I. Dedukhova, Yu. N. Antonenko & V. P. Skulachev

  2. Lomonosov Moscow State University, Faculty of Chemistry, 119991, Moscow, Russia

    N. V. Sumbatyan

  3. Lomonosov Moscow State University, Institute of Mitoengineering, 119991, Moscow, Russia

    V. P. Skulachev

Authors
  1. L. S. Khailova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. A. Nazarov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. V. Sumbatyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. A. Korshunova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. I. Rokitskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. I. Dedukhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu. N. Antonenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V. P. Skulachev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu. N. Antonenko.

Additional information

Original Russian Text © L. S. Khailova, P. A. Nazarov, N. V. Sumbatyan, G. A. Korshunova, T. I. Rokitskaya, V. I. Dedukhova, Yu. N. Antonenko, V. P. Skulachev, 2015, published in Biokhimiya, 2015, Vol. 80, No. 12, pp. 1851-1860.

To whom correspondence should be addressed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khailova, L.S., Nazarov, P.A., Sumbatyan, N.V. et al. Uncoupling and toxic action of alkyltriphenylphosphonium cations on mitochondria and the bacterium Bacillus subtilis as a function of alkyl chain length. Biochemistry Moscow 80, 1589–1597 (2015). https://doi.org/10.1134/S000629791512007X

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629791512007X

Keywords

Search

Navigation