Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Mitochondrial-Targeted Plastoquinone Derivatives. Effect on Senescence and Acute Age-Related Pathologies

Author(s): M. V. Skulachev, Y. N. Antonenko, V. N. Anisimov, B. V. Chernyak, D. A. Cherepanov, V. A. Chistyakov, M. V. Egorov, N. G. Kolosova, G. A. Korshunova, K. G. Lyamzaev, E. Y. Plotnikov, V. A. Roginsky, A. Y. Savchenko, I. I. Severina, F. F. Severin, T. P. Shkurat, V. N. Tashlitsky, K. M. Shidlovsky, M. Y. Vyssokikh, A. A. Zamyatnin, D. B. Zorov and V. P. Skulachev

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

Keywords: Electric potential difference, mitochondria, drug targeting, antioxidant, plastoquinone, ischemia/reperfusion, kidney, rhabdomyolysis, cataract, retinopathies

Abstract:

Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H2 from its oxidized form that appears as a result of the antioxidant activity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H2O2-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondriamediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast “biochemical suicide” of an organism after a severe metabolic crisis.

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Article Details

VOLUME: 12
ISSUE: 6
Page: [800 - 826]
Pages: 27
DOI: 10.2174/138945011795528859