ИСТИНА

In recent decades there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production [1]. The hypothesis of “mild uncoupling” can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. It has recently been shown that mitochondria-targeted antioxidants (SkQ1, MitoQ) as well as the des-quinone form dodecyltriphenylphosphonium exhibit protonophoric action when added together with free fatty acids [2]. As certain amount of free fatty acids is usually present in living cells, SkQ1 may be considered as a mitochondria-targeted protonophore. In the present study, protonophoric activity of a series of derivatives of cationic Rhodamine 19 (including dodecylrhodamine C12R1 and its conjugate with plastoquinone SkQR1) but not of similar derivatives of rhodamine B was revealed using a variety of assays. SkQR1 has better membrane permeability than triphenylphosphonium-based SkQ1 [3]. Derivatives of Rhodamine 19 show protonophoric uncoupling effect even in the absence of fatty acids. It was shown that in planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H+ ions was generated in the presence of C12R1 and SkQR1. These compounds stimulated respiration of rat liver mitochondria and decreased their membrane potential accompanied by partially inhibition of oxidative phosphorylation. As these rhodamine 19-based compounds can accumulate in mitochondria in a Δψ–dependent fashion, they can be considered as mitochondria-targeted cationic uncouplers. Due to the very fact that the accumulation results in uncoupling which, in turn, lowers Δψ, novel uncouplers look as uncouplers of self-limited activity, i.e. mild uncouplers.