Two mechanisms of antioxidant activity of SkQs

F.F. Severin, Y.N. Antonenko, I.I. Severina,
E.A. Smirnova, D.A. Knorre, N.K. Isaev,
E.Y. Plotnikov, D.B. Zorov, V.P. Skulachev
Belozersky Institute of Physico-Chemical Biology and Institute of Mitoengineering, Moscow State University, Moscow

SkQ-type molecules consist of plastoquinone and positively charged hydrophobic "tail". SkQs display two basic activities: they deliver the rechargeable antioxidant to mitochondria and they also act as mitochondrially-targeted protonophores. The latter activity depends on the non-quinone part and is self-inhibitory ("mild") because the molecules are positively-charged. The hydrophobic "tails" of SkQs can transfer protons across membranes in two ways. It was found that the molecules can catalyze the free fatty acid–driven proton flux across the membranes. At least one molecule of this type, C12-Rh19, can also act as a cationic protonophore, i.e. to cross membranes in both neutral and charged (protonated) forms. As both hyper-polarization and deep depolarization of mitochondria were shown to cause reactive oxygen species (ROS) accumulation, mild protonophoric activity of SkQ may contribute to its antioxidant properties. To explore this, we studied the antioxidant effects of the hydrophobic tails in vitro and in vivo. It was found that both the conventional protonophore (FCCP) and C12-Rh19 improve the survival in the model of yeast cell death driven by mitochondrial hyperpolarization. As expected, the concentration window for C12-Rh19 was much (approximately twenty times) wider than for FCCP.
There are established experimental models of death of rats which are mediated by mitochondrial ROS accumulation, e.g. the ones caused by infarctions of kidney or brain. It was found that SkQ-Rh19 significantly improves the survival in these models. Here we show that the non-quinone part of this molecule (C12-Rh19) also active as the death protector: its effect is approximately two-fold lower than that of SkQ-Rh19.
Importantly, the quinone moiety of SkQs can act as pro-oxidant when overdosed. Therefore, hydrophobic tails of SkQs are medically-promising antioxidant compounds. It is tempting to speculate that they also can be used as mimetics of caloric restriction.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010