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Mitochondrial Targeting of Antioxidants

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Systems Biology of Free Radicals and Antioxidants

Abstract

The mitochondrial matrix is the only intracellular compartment that is negatively charged compared to the cytosol. This is why any cation penetrating the mitochondrial membrane must be accumulated inside mitochondria. This principle was used to construct mitochondria-targeted antioxidants (mtAOX) composed of an antioxidant moiety and a penetrating cation with delocalized positive charge. The mtAOX most active in various in vitro tests are MitoQ and SkQ, cationic derivatives of mitochondrial ubiquinone and chloroplast plastoquinone, respectively. Their high activities are due to the fact that the reduced (active) form of MitoQ and SkQ can be regenerated by the mitochondrial respiratory chain from their oxidized forms produced as a result of the antioxidant action of these quinones. An additional important advantage of SkQ is that the “window” between anti- and prooxidant activities of this compound is very much wider than that of MitoQ. Both MitoQ and SkQ have already been tested on animals to treat various diseases that seem to be caused by reactive oxygen species (ROS) produced by mitochondria. In several cases, the use of SkQ was more successful than MitoQ. In particular, it was found that SkQ prolongs the life span of various organisms (from fungi to mammals) and retards (sometimes even reverses) a group of traits typical for aging. Clinical trials of drops of an aqueous solution of SkQ as a medicine have already given a positive result in the case of the age-related disease “dry-eye syndrome.” The SkQ1-containing drops of Visomitin are now available in Russian drugstores.

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Abbreviations

BLM:

Bilayer phospholipid membranes

C12R1:

Dodecylrhodamine 19

C12TPP:

Dodecyltriphenylphosphonium

DMQ:

3-demethoxy ubiquinonyl decyltriphenylphosphonium

ETC:

Mitochondrial electron transport chain

GSH-Px:

Glutathione peroxidase

GSSG-R:

Glutathione reductase

HO• :

Hydroxyl radical

IR:

Ischemia–reperfusion

LP:

Low pathogen

MDA:

Malondialdehyde

MitoBMPO:

Mitochondria-targeted spin trap 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide

MitoDEPMPO:

Mitochondria-targeted spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide

MitoPBN:

Mitochondria-targeted derivative of spin trap α-phenyl-N-tert-butylnitrone

MitoQ:

[10-(6′-ubiquinonyl)] decyltriphenylphosphonium

MitoQH2 :

Reduced form of MitoQ

MitoSOD:

Mitochondria-targeted version of the superoxide dismutase mimetic M40403

MitoSpin:

Mitochondria-targeted spin trap 3′,3′-dibutyl-2′-oxy-3′H-isoindol-5′-yloxy)butyl

MitoVitE:

[2-(3′,4′-dihydro-6′-hydroxy-2′,5′,7′,8′-tetramethyl-2H-1-benzopyran-2′-yl)ethyl] triphenylphosphonium

mtAOX:

Mitochondria-targeted antioxidants

NAC:

N-acetylcysteine

O2 •− :

Superoxide anion

ROS:

Reactive oxygen species

SkQ:

Cationic derivative of plastoquinone or methylplastoquinone

SkQ2M:

Plastoquinonyl decylmethylcarnitine

SkQ3:

5-methyl plastoquinonyl decyltriphenylphosphonium

SkQ4:

Plastoquinonyl decyltributylammonium

SkQB:

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

SkQH2 :

Reduced form of SkQ

SkQP:

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

SkQR1:

10-(6′-plastoquinonyl) decylrhodamine 19

SkQR4:

10-(6′-plastoquinonyl) decylrhodamine B

SOD:

Superoxide dismutase

SPF:

Specific pathogen free

TEMPO/TEMPOL:

Mitochondria-targeted nitroxides

Δψ:

Transmembrane electric potential difference

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Authors and Affiliations

  1. Institute of Mitoengineering, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow, 119991, Russia

    R. A. Zinovkin, M. V. Egorov, V. N. Manskikh, A. A. Zamyatnin Jr. & M. V. Skulachev

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow, 119991, Russia

    L. E. Bakeeva, B. V. Chernyak, N. K. Isaev, G. A. Korshunova, E. Y. Plotnikov, A. A. Zamyatnin Jr., D. B. Zorov & V. P. Skulachev

  3. Institute of Cytology and Genetics, Lavrentiev Avenue 10, Novosibirsk, 630090, Russia

    N. G. Kolosova & M. P. Moshkin

  4. Severtsev Institute of Ecology and Evolution, Leninsky Avenue 33, Moscow, 119071, Russia

    K. A. Rogovin

  5. FSA Therapeutic Products Regulatory Research Center, Petrovsky bulv. 8, Moscow, 103051, Russia

    A. Y. Savchenko

  6. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow, 119991, Russia

    V. P. Skulachev

Authors
  1. R. A. Zinovkin
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  2. L. E. Bakeeva
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  3. B. V. Chernyak
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  4. M. V. Egorov
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  5. N. K. Isaev
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  6. N. G. Kolosova
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  7. G. A. Korshunova
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  8. V. N. Manskikh
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  9. M. P. Moshkin
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  10. E. Y. Plotnikov
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  11. K. A. Rogovin
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  12. A. Y. Savchenko
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  13. A. A. Zamyatnin Jr.
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  14. D. B. Zorov
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  15. M. V. Skulachev
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  16. V. P. Skulachev
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Corresponding author

Correspondence to V. P. Skulachev .

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Editors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

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Zinovkin, R.A. et al. (2014). Mitochondrial Targeting of Antioxidants. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_9

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