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Novel mitochondria-targeted compounds composed of natural constituents: Conjugates of plant alkaloids berberine and palmatine with plastoquinone

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Abstract

Novel mitochondria-targeted compounds composed entirely of natural constituents have been synthesized and tested in model lipid membranes, in isolated mitochondria, and in living human cells in culture. Berberine and palmatine, penetrating cations of plant origin, were conjugated by nonyloxycarbonylmethyl residue with the plant electron carrier and antioxidant plastoquinone. These conjugates (SkQBerb, SkQPalm) and their analogs lacking the plastoquinol moiety (C10Berb and C10Palm) penetrated across planar bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria in living human cells in culture. Reduced forms of SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In isolated mitochondria and in living cells, the berberine and palmatine moieties were not reduced, so antioxidant activity belonged exclusively to the plastoquinol moiety. In human fibroblasts, nanomolar SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by exogenous hydrogen peroxide. At higher concentrations, conjugates of berberine and palmatine induced proton transport mediated by free fatty acids both in model and in mitochondrial membrane. In mitochondria this process was facilitated by the adenine nucleotide carrier. As an example of application of the novel mitochondria-targeted antioxidants SkQBerb and SkQPalm to studies of signal transduction, we discuss induction of cell cycle arrest, differentiation, and morphological normalization of some tumor cells. We suggest that production of oxygen radicals in mitochondria is necessary for growth factors-MAP-kinase signaling, which supports proliferation and transformed phenotype.

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Abbreviations

ANT:

adenine nucleotide translocase

AMVN:

2,2′-azodi(2,4′-dimethylvaleronitrile)

BLM:

bilayer phospholipid membrane

C10Berb:

13-(decyloxycarbonylmethyl)berberine

CM-DCF-DA:

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

C10Palm:

13-(decyloxycarbonylmethyl)palmatine

C12TPP:

dodecyltriphenylphosphonium

FA:

fatty acid

FCCP:

trifluoromethoxycarbonylcyanide phenylhydrazone

ROS:

reactive oxygen species

SkQ1:

10-(6′-plastoquinonyl)decyltriphen-ylphosphonium

SkQBerb:

13-[9-(6′-plastoquinonyl)nonyloxycarbonylmethyl]berberine

SkQPalm:

13-[9-(6′-plastoquinonyl)nonyloxycarbonylmethyl]palmatine

SkQR1:

10-(6′-plastoquinonyl)decylrhodamine 19

TPP+ :

triphenylphosphonium

ΔΨ :

transmembrane electric potential difference

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Authors and Affiliations

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

    B. V. Chernyak, Y. N. Antonenko, E. R. Galimov, L. V. Domnina, V. B. Dugina, O. Yu. Ivanova, D. S. Izyumov, K. G. Lyamzaev, A. V. Pustovidko, T. I. Rokitskaya, I. I. Severina, R. A. Simonyan, M. V. Skulachev, V. N. Tashlitsky, E. V. Titova & G. S. Shagieva

  2. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33, 119071, Moscow, Russia

    R. A. Zvyagilskaya, A. G. Rogov & T. A. Trendeleva

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  1. B. V. Chernyak
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  2. Y. N. Antonenko
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  3. E. R. Galimov
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  4. L. V. Domnina
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  5. V. B. Dugina
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  6. R. A. Zvyagilskaya
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  7. O. Yu. Ivanova
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  8. D. S. Izyumov
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  9. K. G. Lyamzaev
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  10. A. V. Pustovidko
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  11. T. I. Rokitskaya
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  12. A. G. Rogov
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  13. I. I. Severina
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  14. R. A. Simonyan
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  15. M. V. Skulachev
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  16. V. N. Tashlitsky
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  17. E. V. Titova
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  18. T. A. Trendeleva
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  19. G. S. Shagieva
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Correspondence to B. V. Chernyak.

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Published in Russian in Biokhimiya, 2012, Vol. 77, No. 9, pp. 1186–1200.

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Chernyak, B.V., Antonenko, Y.N., Galimov, E.R. et al. Novel mitochondria-targeted compounds composed of natural constituents: Conjugates of plant alkaloids berberine and palmatine with plastoquinone. Biochemistry Moscow 77, 983–995 (2012). https://doi.org/10.1134/S0006297912090040

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