Uncoupling and Toxic Action of Alkyltriphenylphosphonium Cations on Mitochondria and the Bacterium Bacillus subtilis as a Function of Alkyl Chain Length

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L. S. Khailova¹, P. A. Nazarov¹, N. V. Sumbatyan², G. A. Korshunova¹, T. I. Rokitskaya¹, V. I. Dedukhova¹, Yu. N. Antonenko^1*, and V. P. Skulachev^1,3

¹Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, 119991 Moscow, Russia; E-mail: antonen@belozersky.msu.ru; antonen@genebee.msu.ru

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

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

^* To whom correspondence should be addressed.

Received February 17, 2015; Revision received July 8, 2015

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A series of permeating cations based on alkyl derivatives of triphenylphosphonium (C_n-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 C_n-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 C_n-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 C_n-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.

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KEY WORDS: permeating cation, SkQ1, mitochondria, uncoupling, bacteria, cytotoxicity

DOI: 10.1134/S000629791512007X

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