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Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants — the “Skulachev-ion” derivatives

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Abstract

Production of reactive oxygen species (ROS) in mitochondria was studied using the novel mitochondria-targeted antioxidants (SkQ) in cultures of human cells. It was shown that SkQ rapidly (1–2 h) and selectively accumulated in mitochondria and prevented oxidation of mitochondrial components under oxidative stress induced by hydrogen peroxide. At nanomolar concentrations, SkQ inhibited oxidation of glutathione, fragmentation of mitochondria, and translocation of Bax from cytosol into mitochondria. The last effect could be related to prevention of conformational change in the adenine nucleotide transporter, which depends on oxidation of critical thiols. Mitochondria-targeted antioxidants at nanomolar concentrations prevented accumulation of ROS and cell death under oxidative stress. These effects required 24 h or more (depending on the cell type) preincubation, and this was not related to slow induction of endogenous antioxidant systems. It is suggested that SkQ slowly accumulates in a small subpopulation of mitochondria that have decreased membrane potential and produce the major part of ROS under oxidative stress. This population was visualized in the cells using potential-sensitive dye. The possible role of the small fraction of “bad” mitochondria in cell physiology is discussed.

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Abbreviations

ANT:

adenine nucleotide translocator

CM-DCF-DA:

5-(-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate

C12TPP:

dodecyltriphenylphosphonium

FCCP:

carbonyl cyanide p-trifluoromethoxyphenylhydrazone

ROS:

reactive oxygen species

SkQ:

cationic derivative of plastoquinone

SkQ1:

10-(6′-plastoquinonyl) decyltriphenylphosphonium

SkQR1:

10-(6′-plastoquinonyl) decylrhodamine 19

TMRM:

tetramethylrhodamine methyl ester

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Authors and Affiliations

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

    D. S. Izyumov, L. V. Domnina, O. K. Nepryakhina, A. V. Avetisyan, S. A. Golyshev, O. Y. Ivanova, M. V. Korotetskaya, K. G. Lyamzaev, O. Y. Pletjushkina, E. N. Popova & B. V. Chernyak

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  1. D. S. Izyumov
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  2. L. V. Domnina
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  3. O. K. Nepryakhina
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  4. A. V. Avetisyan
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  5. S. A. Golyshev
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  6. O. Y. Ivanova
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  7. M. V. Korotetskaya
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  8. K. G. Lyamzaev
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  9. O. Y. Pletjushkina
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  11. B. V. Chernyak
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Correspondence to B. V. Chernyak.

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Published in Russian in Biokhimiya, 2010, Vol. 75, No. 2, pp. 149–157.

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Izyumov, D.S., Domnina, L.V., Nepryakhina, O.K. et al. Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants — the “Skulachev-ion” derivatives. Biochemistry Moscow 75, 123–129 (2010). https://doi.org/10.1134/S000629791002001X

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  • DOI: https://doi.org/10.1134/S000629791002001X

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