Abstract
Mitochondria are involved in many processes in eukaryotic cells. They play a central role in energy conservation and participate in cell metabolism and signaling pathways. Mitochondria are the main source of reactive oxygen species, excessive generation of which provokes numerous pathologies and cell death. One of the most promising approaches to the attenuation of oxidative stress in mitochondria is the use of targeted (i.e., transported exclusively into mitochondria) lipophilic cationic antioxidants. These compounds offer advantages over conventional water-soluble antioxidants because they induce the so-called “mild uncoupling” and can prevent collapse of the membrane potential in low, nontoxic concentrations. A novel mitochondria-targeted antioxidant, SkQT1, was synthesized and tested within the framework of the research project guided by V. P. Skulachev. The results of these experiments were initially reported in 2013; however, one publication was not able to accommodate all the data on the SkQT1 interactions with isolated mitochondria and cells. Here, we examined comparative effects of SkQT1 and SkQ1 on rat liver mitochondria (with broader spectrum of energy parame- ters being studied) and yeast cells. SkQT1 was found to be less effective uncoupler, depolarizing agent, inhibitor of respiration and ATP synthesis, and “opener” of a nonspecific pore compared to SkQ1. At the same time SkQ1 exhibited higher antioxidant activity. Both SkQT1 and SkQ1 prevented oxidative stress and mitochondria fragmentation in yeast cells exposed to t-butyl hydroperoxide and promoted cell survival, with SkQT1 being more efficient than SkQ1. Together with the results presented in 2013, our data suggest that SkQT1 is the most promising mitochondria-targeted antioxidant that can be used for preventing various pathologies associated with the oxidative stress in mitochondria.
Similar content being viewed by others
Abbreviations
- Ap5A:
-
P1,P5-di(adenosine-5′)pentaphosphate
- CCCP:
-
carbonyl cyanide m-chlorophenylhydrazone
- CsA:
-
cyclosporin A
- mPTP:
-
mitochondrial permeability transition pore
- ROS:
-
reactive oxygen species
- SkQ1:
-
10-(6′-plasto-quinonyl)decyltriphenylphosphonium
- SkQT1:
-
a mixture of SkQT1(p) and SkQT1(m) in a proportion of 1.4: 1
- SkQT1(m):
-
10-(5′-toluquinonyl)decyltriphenylphosphonium
- SkQT1(p):
-
10-(6′-toluquinonyl)decyltriphenylphosphonium
- t-BHP:
-
tert-butyl hydroperoxide
- ΔΨ:
-
transmembrane electric potential difference
References
Zhang, Y., and Avalos, J. L. (2017) Traditional and novel tools to probe the mitochondrial metabolism in health and disease, Wiley Interdiscip. Rev. Syst. Biol. Med., 9.
Dudek, J. (2017) Role of cardiolipin in mitochondrial sig-naling pathways, Front. Cell. Dev. Biol., 5, 90.
Dhingra, R., and Kirshenbaum, L. A. (2014) Regulation of mitochondrial dynamics and cell fate, Circ. J., 78, 803–810.
Sander, L. E., and Garaude, J. (2017) The mitochondrial respiratory chain: a metabolic rheostat of innate immune cell-mediated antibacterial responses, Mitochondrion, pii: S1567–7249.
Georgieva, E., Ivanova, D., Zhelev, Z., Bakalova, R., Gulubova, M., and Aoki, I. (2017) Mitochondrial dysfunc-tion and redox imbalance as a diagnostic marker of “free radical diseases”, Anticancer Res., 37, 5373–5381.
Mailloux, R. J. (2016) Application of mitochondria-target-ed pharmaceuticals for the treatment of heart disease, Curr. Pharm. Des., 22, 4763–4779.
Wang, C. H., Wu, S. B., Wu, Y. T., and Wei, Y. H. (2013) Oxidative stress response elicited by mitochondrial dys-function: implication in the pathophysiology of aging, Exp. Biol. Med. (Maywood), 238, 450–460.
Skulachev, V. P., Anisimov, V. N., Antonenko, Y. N., Bakeeva, L. E., Chernyak, B. V., Erichev, V. P., Filenko, O. F., Kalinina, N. I., Kapelko, V. I., Kolosova, N. G., Kopnin, B. P., Korshunova, G. A., Lichinitser, M. R., Obukhova, L. A., Pasyukova, E. G., Pisarenko, O. I., Roginsky, V. A., Ruuge, E. K., Senin, I. I., Severina, I. I., Skulachev, M. V., Spivak, I. M., Tashlitsky, V. N., Tkachuk, V. A., Vyssokikh, M. Y., Yaguzhinsky, L. S., and Zorov, D. B. (2009) An attempt to prevent senescence: a mitochondr-ial approach, Biochim. Biophys. Acta, 1787, 437–461.
Murphy, M. P., and Smith, R. A. J. (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations, Annu. Rev. Pharmacol. Toxicol., 47, 629–656.
Skulachev, V. P. (2007) A biochemical approach to the problem of aging: “megaproject” on membrane-penetrat-ing ions. The first results and prospects, Biochemistry (Moscow), 72, 1385–1396.
Green, D. E. (1974) The electromechanochemical model for energy coupling in mitochondria, Biochim. Biophys. Acta, 346, 27–78.
Severina, I. I., Severin, F. F., Korshunova, G. A., Sumbatyan, N. V., Ilyasova, T. M., Simonyan, R. A., Rogov, A. G., Trendeleva, T. A., Zvyagilskaya, R. A., Dugina, V. B., Domnina, L. V., Fetisova, E. K., Lyamzaev, K. G., Vyssokikh, M. Y., Chernyak, B. V., Skulachev, M. V., Skulachev, V. P., and Sadovnichii, V. A. (2013) In search of novel highly active mitochondria-targeted antioxidants: thymoquinone and its cationic derivatives, FEBS Lett., 587, 2018–2024.
Institute for Laboratory Animal Research (2011) Guide for the Care and Use of Laboratory Animals, National Academies Press (US), Washington (DC).
Rogov, A. G., Trendeleva, T. A., Aliverdieva, D. A., and Zvyagilskaya, R. A. (2016) More about interactions of rho-damine 19 butyl ester with rat liver mitochondria, Biochemistry (Moscow), 81, 432–438.
Chance, B., and Williams, G. R. (1955) A simple and rapid assay of oxidative phosphorylation, Nature, 175, 1120–1121.
Akerman, K. E., and Wikstrom, M. K. (1976) Safranine as a probe of the mitochondrial membrane potential, FEBS Lett., 68, 191–197.
Bernardi, P., Krauskof, A., Basso, E., Petronilli, V., Blachly-Dyson, E., Di Lisa, F., and Forte, M. A. (2006) The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J., 273, 2077–2099.
Zharova, T. V., and Vinogradov, A. D. (2006) Energy-linked binding of Pi is required for continuous steady-state pro-ton-translocating ATP hydrolysis catalyzed by F0F1 ATP synthase, Biochemistry, 45, 14552–14558.
Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utiliz-ing the principle of protein-dye binding, Anal. Biochem., 72, 248–254.
Zviagil'skaya, R. A., Zelenshchikova, V. A., Ural'skaya, L. A., and Kotel'nikova, A. V. (1981) Respiratory system of Endomyces magnusii. Properties of mitochondria from cells grown on glycerol, Biochemistry (Moscow), 46, 3–10.
Adamikova, L., Griac, P., Tomaska, L., and Nosek, J. (1998) Development of a transformation system for the multinuclear yeast Dipodascus (Endomyces) magnusii, Yeast, 14, 805–812.
Agnello, M., Morici, G., and Rinaldi, A. M. (2008) A method for measuring mitochondrial mass and activity, Cytotechnology, 56, 145–149.
Puleston, D. (2015) Detection of mitochondrial mass, damage, and reactive oxygen species by flow cytometry, Cold Spring Harb. Protoc., doi:10.1101/pdb.prot086298.
Mukhopadhyay, P., Rajesh, M., Hasko, G., Hawkins, B. J., Madesh, M., and Pacher, P. (2007) Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy, Nature Protocols, 2, 2295–2301.
Sukhanova, E. I., Trendeleva, T. A., and Zvyagilskaya, R. A. (2010) Interaction of yeast mitochondria with fatty acids and mitochondria-targeted lipophilic cations, Biochemistry (Moscow), 75, 139–144.
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.
Skulachev, V. P. (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants, Q. Rev. Biophys., 29, 169–202.
Starkov, A. A. (1997) “Mild” uncoupling of mitochondria, Biosci. Rep., 17, 273–279.
Skulachev, V. P. (1998) Uncoupling: new approaches to an old problem of bioenergetics, Biochim. Biophys. Acta, 1363, 100–124.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published in Russian in Biokhimiya, 2018, Vol. 83, No. 5, pp. 724–734.
Rights and permissions
About this article
Cite this article
Rogov, A.G., Goleva, T.N., Trendeleva, T.A. et al. New Data on Effects of SkQ1 and SkQT1 on Rat Liver Mitochondria and Yeast Cells. Biochemistry Moscow 83, 552–561 (2018). https://doi.org/10.1134/S0006297918050085
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297918050085