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Abstract
The synthesis of a mitochondria-targeted derivative of the classical mitochondrial uncoupler carbonyl cyanide-m-chlorophenylhydrazone (CCCP) by alkoxy substitution of CCCP with n-decyl(triphenyl)phosphonium cation yielded mitoCCCP, which was able to inhibit the uncoupling action of CCCP, tyrphostin A9 and niclosamide on rat liver mitochondria, but not that of 2,4-dinitrophenol, at a concentration of 1-2 μM. MitoCCCP did not uncouple mitochondria by itself at these concentrations, although it exhibited uncoupling action at tens of micromolar concentrations. Thus, mitoCCCP appeared to be a more effective mitochondrial recoupler than 6-ketocholestanol. Both mitoCCCP and 6-ketocholestanol did not inhibit the protonophoric activity of CCCP in artificial bilayer lipid membranes, which might compromise the simple proton-shuttling mechanism of the uncoupling activity on mitochondria.
Highlights
It is 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
The recoupling effect of 6-ketocholestanol found earlier by Starkov and colleagues [10, 11] 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) [9]
The amino group was converted into a diazonium salt by a diazotization reaction, and a functional group responsible for the uncoupling activity of CCCP was formed by the nucleophilic addition of malononitrile
Summary
It is 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. The recoupling effect of 6-ketocholestanol (kCh) found earlier by Starkov and colleagues [10, 11] 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) [9]. This idea was supported by the fact that in planar bilayer lipid membranes, kCh failed to reverse the protonophoric action of SF6847, but even enhanced the conductivity increase caused by this uncoupler. We report synthesis of a mitochondria-targeted derivative of CCCP (a conjugate with TPP coined mitoCCCP), which appeared to be a rather weak uncoupler but exhibited effective inhibition of the CCCPcaused uncoupling in mitochondria
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