Biochemistry (Moscow)

, Volume 73, Issue 12, pp 1273–1287 | Cite as

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: Synthesis and in vitro studies

  • Y. N. Antonenko
  • A. V. Avetisyan
  • L. E. Bakeeva
  • B. V. Chernyak
  • V. A. Chertkov
  • L. V. Domnina
  • O. Yu. Ivanova
  • D. S. Izyumov
  • L. S. Khailova
  • S. S. Klishin
  • G. A. Korshunova
  • K. G. Lyamzaev
  • M. S. Muntyan
  • O. K. Nepryakhina
  • A. A. Pashkovskaya
  • O. Yu. Pletjushkina
  • A. V. Pustovidko
  • V. A. Roginsky
  • T. I. Rokitskaya
  • E. K. Ruuge
  • V. B. Saprunova
  • I. I. Severina
  • R. A. Simonyan
  • I. V. Skulachev
  • M. V. Skulachev
  • N. V. Sumbatyan
  • I. V. Sviryaeva
  • V. N. Tashlitsky
  • J. M. Vassiliev
  • M. Yu. Vyssokikh
  • L. S. Yaguzhinsky
  • A. A. ZamyatninJr.
  • V. P. Skulachev
Article

Abstract

Synthesis of cationic plastoquinone derivatives (SkQs) containing positively charged phosphonium or rhodamine moieties connected to plastoquinone by decane or pentane linkers is described. It is shown that SkQs (i) easily penetrate through planar, mitochondrial, and outer cell membranes, (ii) at low (nanomolar) concentrations, posses strong antioxidant activity in aqueous solution, BLM, lipid micelles, liposomes, isolated mitochondria, and cells, (iii) at higher (micromolar) concentrations, show pronounced prooxidant activity, the “window” between anti- and prooxidant concentrations being very much larger than for MitoQ, a cationic ubiquinone derivative showing very much lower antioxidant activity and higher prooxidant activity, (iv) are reduced by the respiratory chain to SkQH2, the rate of oxidation of SkQH2 being lower than the rate of SkQ reduction, and (v) prevent oxidation of mitochondrial cardiolipin by OH·. In HeLa cells and human fibroblasts, SkQs operate as powerful inhibitors of the ROS-induced apoptosis and necrosis. For the two most active SkQs, namely SkQ1 and SkQR1, C1/2 values for inhibition of the H2O2-induced apoptosis in fibroblasts appear to be as low as 1·10−11 and 8·10−13 M, respectively. SkQR1, a fluorescent representative of the SkQ family, specifically stains a single type of organelles in the living cell, i.e. energized mitochondria. Such specificity is explained by the fact that it is the mitochondrial matrix that is the only negatively-charged compartment inside the cell. Assuming that the Δψ values on the outer cell and inner mitochondrial membranes are about 60 and 180 mV, respectively, and taking into account distribution coefficient of SkQ1 between lipid and water (about 13,000: 1), the SkQ1 concentration in the inner leaflet of the inner mitochondrial membrane should be 1.3·108 times higher than in the extracellular space. This explains the very high efficiency of such compounds in experiments on cell cultures. It is concluded that SkQs are rechargeable, mitochondria-targeted antioxidants of very high efficiency and specificity. Therefore, they might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo.

Key words

SkQ1 penetrating cations plastoquinone antioxidants mitochondria apoptosis 

Abbreviations

Δψ

transmembrane electric potential difference

AAPH

2,2′-azobis(2-amidinopropane) dihydrochloride

BLM

bilayer planar phospholipid membrane

BSA

bovine serum albumin

CCCP

carbonyl cyanide m-chlorophenylhydrazone

CM-DCF-DA

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

C12TPP

dodecyltriphenylphosphonium

DMQ

demethoxy-derivative of CoQ0 lacking one of the methoxy groups

DPQ

decylplastoquinone

FCCP

carbonyl cyanide p-trifluo-romethoxyphenylhydrazone

MDA

malondialdehyde

MitoQ

10-(6′-ubiquinonyl) decyltriphenylphosphonium

NAC

N-acetyl cysteine

PQ

plastoquinone

ROS

reactive oxygen species

SF6846

3,5-di(tert)butyl-4-hydroxybenzylidene malononitrile

SkQ

cationic derivative of plastoquinone or methyl plastoquinone

SkQ1

10-(6′-plastoquinonyl) decyltriphenylphosphonium

SkQ2

10-(6′-plastoquinonyl) decylcarnitine

SkQ2M

10-(6t′-plastoquinonyl) decylmethylcarnitine

SkQ3

10-(6′-methylplasto-quinonyl) decyltriphenylphosphonium

SkQ4

10-(6′-plastoquinonyl) decyltributylammonium

SkQ5

5-(6′-plastoquinonyl) amyltriphenylphosphonium

SkQR1

10-(6′-plastoquinonyl) decylrhodamine 19

TMRE

tetramethylrhodamine ethyl ester

TPB

tetraphenylborate

TPP

tetraphenylphosphonium

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Copyright information

© MAIK Nauka 2008

Authors and Affiliations

  • Y. N. Antonenko
    • 1
  • A. V. Avetisyan
    • 1
  • L. E. Bakeeva
    • 1
  • B. V. Chernyak
    • 1
  • V. A. Chertkov
    • 2
  • L. V. Domnina
    • 1
  • O. Yu. Ivanova
    • 1
  • D. S. Izyumov
    • 1
  • L. S. Khailova
    • 1
  • S. S. Klishin
    • 1
  • G. A. Korshunova
    • 1
  • K. G. Lyamzaev
    • 1
  • M. S. Muntyan
    • 1
  • O. K. Nepryakhina
    • 1
  • A. A. Pashkovskaya
    • 1
  • O. Yu. Pletjushkina
    • 1
  • A. V. Pustovidko
    • 1
  • V. A. Roginsky
    • 3
  • T. I. Rokitskaya
    • 1
  • E. K. Ruuge
    • 4
  • V. B. Saprunova
    • 1
  • I. I. Severina
    • 5
  • R. A. Simonyan
    • 1
  • I. V. Skulachev
    • 6
  • M. V. Skulachev
    • 6
  • N. V. Sumbatyan
    • 2
  • I. V. Sviryaeva
    • 4
  • V. N. Tashlitsky
    • 2
  • J. M. Vassiliev
    • 1
  • M. Yu. Vyssokikh
    • 1
  • L. S. Yaguzhinsky
    • 1
  • A. A. ZamyatninJr.
    • 6
  • V. P. Skulachev
    • 1
    • 6
    • 7
  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  2. 2.Chemical FacultyLomonosov Moscow State UniversityMoscowRussia
  3. 3.Institute of Chemical PhysicsMoscowRussia
  4. 4.Institute of Experimental CardiologyCardiology Research CenterMoscowRussia
  5. 5.Biological FacultyLomonosov Moscow State UniversityMoscowRussia
  6. 6.Mitoengineering CenterLomonosov Moscow State UniversityMoscowRussia
  7. 7.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia

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