Untitled

Abstract

The respiratory uncouplers carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and carbonyl cyanide m-chlorophenylhydrazone (CCCP) affect the activities of two mitochondrial ion channels from mouse liver. At micromolar concentrations, the phenylhydrazones block the voltage-dependent 100-pS channel, mCS, and induce the multiple-conductance-level channel, MCC. The binding site(s) involved in perturbation of channel activities are probably distinct from the sites involved in uncoupling of oxidative phosphorylation which occurs at nanomolar concentrations of the phenylhydrazones. The effects of FCCP and CCCP on the mitochondrial ion channels could be partially reversed by washing with fresh media and were always reversed by perfusion with dithiothreitol. These results indicate that the effects of the phenylhydrazones on mitochondrial ion channels may be related to the ability of these compounds to act as sulfhydryl reagents and not to their protonophoric and uncoupling activity.

Carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP) induces initiation factor 2α phosphorylation and translation inhibition in PC12 cells

“…FCCP is known to bind sulfhydryl groups and react with aminothiols, the direct interactions with the PTP channel proteins being the mechanism causing PTP opening [12]. In general, these reactions can be prevented by dithiothreitol (DTT), which is capable to react with phenylhydrazones such as FCCP [12]. Consistently with this mechanism, the FCCP‐induced eIF2α phosphorylation in PC12 cells diminished by DTT treatment (Fig.…”

“…To explore the potential role of mitochondrial dysfunction in translational regulation, we used the respiratory uncoupler FCCP which induces significant [Ca 2+ ] i increase through mitochondrial PTP opening [12]. As shown in Fig.…”

“…It is widely accepted that the ATP/ADP antiporter is a component of the PTP assembly, and that the redox state of two of its thiol groups plays a crucial role in PTP function [4]. FCCP is known to bind sulfhydryl groups and react with aminothiols, the direct interactions with the PTP channel proteins being the mechanism causing PTP opening [12]. In general, these reactions can be prevented by dithiothreitol (DTT), which is capable to react with phenylhydrazones such as FCCP [12].…”

“…Thus, to gain insight into the mechanism of the ischemia‐induced eIF2α phosphorylation here we studied whether the mitochondrial dysfunction as reported in ischemia plays a role in the observed eIF2(αP) accumulation. Hence, NGF‐differentiated PC12 cells were treated with the oxidative phosphorylation uncoupler carbonyl cyanide p ‐trifluoromethoxyphenylhydrazone (FCCP) [12].…”

Overexpression of Bcl‐2 suppresses the calcium activation of a mitochondrial megachannel

“…Compounds that induce the permeability transition in isolated mitochondria often cause apoptosis. MCC is blocked by the anti‐apoptotic drug cyclosporin [29,32] and several other compounds known to inhibit the PTP [33,34], and opened by uncouplers [35]. In general, the pharmacology of MCC is consistent with its assignment as the pore underlying the PTP.…”