Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs)

Abstract

The present state of the art in studies on the mechanisms of antioxidant activities of mitochondria-targeted cationic plastoquinone derivatives (SkQs) is reviewed. Our experiments showed that these compounds can operate as antioxidants in two quite different ways, i.e. (i) by preventing peroxidation of cardiolipin [Antonenko et al., Biochemistry (Moscow) 73 (2008) 1273-1287] and (ii) by fatty acid cycling resulting in mild uncoupling that inhibits the formation of reactive oxygen species (ROS) in mitochondrial State 4 [Severin et al. Proc. Natl. Acad. Sci. USA 107 (2009), 663-668]. The quinol and cationic moieties of SkQ are involved in cases (i) and (ii), respectively. In case (i) SkQH2 interrupts propagation of chain reactions involved in peroxidation of unsaturated fatty acid residues in cardiolipin, the formed SkQ- being reduced back to SkQH2 by heme bH of complex III in an antimycin-sensitive way. Molecular dynamics simulation showed that there are two stable conformations of SkQ1 with the quinol residue localized near peroxyl radicals at C9 or C13 of the linoleate residue in cardiolipin. In mechanism (ii), fatty acid cycling mediated by the cationic SkQ moiety is involved. It consists of (a) transmembrane movement of the fatty acid anion/SkQ cation pair and (b) back flows of free SkQ cation and protonated fatty acid. The cycling results in a protonophorous effect that was demonstrated in planar phospholipid membranes and liposomes. In mitochondria, the cycling gives rise to mild uncoupling, thereby decreasing membrane potential and ROS generation coupled to reverse electron transport in the respiratory chain. In yeast cells, dodecyltriphenylphosphonium (capital ES, Cyrillic12TPP), the cationic part of SkQ1, induces uncoupling that is mitochondria-targeted since capital ES, Cyrillic12TPP is specifically accumulated in mitochondria and increases the H+ conductance of their inner membrane. The conductance of the outer cell membrane is not affected by capital ES, Cyrillic12TPP.

Bioenergetic Effects of Mitochondrial-Targeted Coenzyme Q Analogs in Endothelial Cells

“…The respiratory chain then regenerates the MTQA through redox cycling similar to what occurs for native coenzyme Q. An example of the effectiveness of this process is the prevention of cardiolipin peroxidation in heart mitochondria exposed to iron and ascorbate (Skulachev et al, 2010). On the other hand, redox cycling generates electron leaks to oxygen, leading to pro-oxidant properties as demonstrated in past studies O'Malley et al, 2006;Doughan and Dikalov, 2007).…”

“…In particular, there is a need for better understanding of the bioenergetic effects of targeted CoQ analogs and whether they are direct and/or consequent to their redox properties. There is evidence that MTQAs induce mild respiratory uncoupling through the reduction of mitochondrial membrane potential, possibly a protonophoric effect that may involve fatty acid transport (Skulachev et al, 2009(Skulachev et al, , 2010. However, it is not clear to what extent this translates to bioenergetic action at the intact-cell level.…”

“…The major protective reaction transfers a hydrogen atom (H⅐) from the quinol to a lipid radical (LO 2 ⅐), forming LOOH and generating the semiquinone form of the MTQA Skulachev et al, 2010). The respiratory chain then regenerates the MTQA through redox cycling similar to what occurs for native coenzyme Q.…”

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

“…These compounds penetrate into mitochondrial intermembrane space where they undergo reduction to hydroquinone form by the enzymes of respiratory chain. At low concentrations, SkQ was shown to prevent hydroxyl-radical-mediated cardiolipin peroxidation and inhibited ROS-induced apoptosis and necrosis of human fibroblasts (7,235).…”

“…The interest in antioxidant properties of quinones became inspiration for synthesis of water-soluble derivatives such as MitoQ or SkQ (7,8,134,235). These compounds penetrate into mitochondrial intermembrane space where they undergo reduction to hydroquinone form by the enzymes of respiratory chain.…”