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

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 SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) 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 H(2)O(2)-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 mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis.

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

“…This influence was detected 24 h after SkQR1 injection . Such relationships can decrease the GSK3β-mediated apoptosis involved in the neuronal Abeta toxic cascade in the brain (Lloret et al, 2011;Skulachev et al, 2011).…”

“…Mitochondria-targeted antioxidants include substances such as SkQ, MitoQ, MitoVitE, MitoPBN, MitoPeroxidase, glutathione choline esters, latrepirdine, and Szeto-Schiller (SS) peptides (Manczak et al, 2010;McManus et al, 2011;Skulachev et al, 2011;Calkins et al, 2012). One SkQ derivative, namely SkQ1, was the first mitochondria-targeted drug employed in medical practice (Yani et al, 2012).…”

“…It has been previously demonstrated that very low concentrations of mitochondria-targeted antioxidants exhibit highly efficient antioxidant activity in aqueous solutions, lipid micelles, liposomes, isolated mitochondria, and cell cultures (Skulachev, 2007;Antonenko et al, 2008a,b;Skulachev et al, 2011). Mitochondria-targeted drugs have been proposed for treatment of mROS-associated pathologies.…”

Novel Mitochondria-Targeted Antioxidants: Plastoquinone Conjugated with Cationic Plant Alkaloids Berberine and Palmatine

“…It was shown that substitution of ubiquinol to plastoquinol significantly improved the antioxidant properties of the compound in model membranes as well as in isolated mitochondria, living cells, and organisms (8). SkQ1was found to be a very efficient agent at preventing a variety of degenerative processes and prolonging the lifespan of fungi, invertebrates, and vertebrates in nanomolar doses (9)(10)(11)(12)(13)(14)(15)). We synthesized and tested several analogs of SkQ1, and in one of them (SkQR1) the phosphonium cation was substituted by the fluorescent cation rhodamine 19.…”

Conservative Treatment of Neurotrophic Keratitis

“…Пластохинонилдецилтрифенилфосфония бромид являет-ся активной субстанцией глазных капель Визомитин, первого в мире зарегистрированного лекарственного препарата с митохондриально-адресованным антиокси-дантом в качестве основного действующего вещества. Учитывая механизм терапевтического действия препара-та Визомитин, нами была рассмотрена возможность его использования у больных с НК [15][16][17][18].…”