Mitochondrial bioenergetics during exposure of rats to perfluidone, a fluorinated arylalkylsulphonamide

Apart from the symptoms of poisoning which the fluorinated arylalkylsulphonamides share with the classical protonphore and uncoupler of oxidative phosphorylation, carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), the direct correlation between the lipophilic weak acid properties of these chemicals and their biological activity suggests that permeation of the inner mitochondrial membrane could be the initial step in the molecular mechanism of their biological activity. Mitochondria isolated from the livers of rats intraperitoneally exposed to varying doses (0-80 mg/kg body wt.) of perfluidone (1,1,1-trifluoro-N-(2 methyl-4-(phenylsulphonyl)phenyl methanesulphonamide), a fluorinated arylalkylsulphonamide pesticide, exhibit the following dose-dependent features: (i) increased state-4 respiration: stimulation being maximal (greater than or equal to 400%) at 80 mg perfluidone per kg body wt.), (ii) release of respiratory control by ADP: least respiratory control ratios (RCRs) (less than or equal to 1.2) were obtained at 80 mg perfluidone per kg body wt., (iii) reduced ADP/O ratios, (iv) increased mitochondrial passive swelling, (vi) reduced rates of mitochondrial proton ejection during succinate oxidation, (vi) reduced rates of respiration-dependent Ca2+ accumulation and (vii) an enhanced oligomycin-sensitive ATPase action. These features which are qualitatively identical to those of the classical protonophore FCCP, suggest that permeation of the inner mitochondrial membrane by perfluidone is accompanied by a movement of protons into the matrix such that the proton motive force required for ATP synthesis and ion transport becomes small or not formed at all.