to avoid adverse effects, it is reasonable to design mitochondria-targeted agents. To make the impact of uncouplers more selective, i.e. By contrast, kCh was ineffective with 2,4-dinitrophenol (DNP), fatty acids and gramicidin A. Later, the kCh-induced recoupling was also reported for curcumin derivatives, eudesman, SR4, a bicyclic hydroquinone and BAM15. an increase in the membrane dipole potential and diminution of membrane fluidity. Nevertheless, it cannot be excluded that the recoupling action of kCh is somehow associated with its impact on physical properties of membranes, i.e. This idea was supported by the fact that in planar bilayer lipid membranes, kCh not only failed to reverse the protonophoric action of SF6847, but even enhanced the conductivity increase caused by this uncoupler. In particular, the recoupling effect of 6-ketocholestanol (kCh) found earlier by Starkov and colleagues was tentatively considered as an evidence in favor of involvement of proteins in mitochondrial uncoupling mediated by such agents as carbonyl cyanide- m-chlorophenylhydrazone (CCCP), carbonyl cyanide p-trifluoromethoxy phenylhydrazone (FCCP) and tyrphostin A9 (SF6847). There is so far no consensus whether the uncoupling action occurs with or without the aid of membrane proteins, despite the general confidence in the protonophoric nature of this action. Although the experiments with uncouplers on artificial membranes, mitochondria and bacteria have played a crucial role in the validation of Mitchell’s chemiosmotic theory, the mechanism of uncoupling remains not fully understood. Compounds that compromise the coupling between respiration and phosphorylation called uncouplers have recently received strong interest as promising anti-cancer, antibacterial, anti-obesity, antidiabetic, neuroprotective and cardioprotective agents. It is now generally accepted that electron transfer via a chain of proton pumps in the inner mitochondrial or bacterial membrane results in the formation of a transmembrane difference of electrochemical potentials of hydrogen ions that couples the oxidation of respiratory substrates to ATP synthesis.
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