Enhancement by tetraphenylboron of inhibition of mitochondrial respiration induced by 1-methyl-4-phenylpyridinium ion (MPP(+)).
The effect of tetraphenylboron (TPB(?)), an activator of a membrane transport of lipophilic cations, on the inhibition of mouse liver mitochondrial respiration induced by a neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), and by some structurally related compounds was studied. Of the compounds tested, MPP(+) and 4-phenylpyridine (4-PP) significantly inhibited the respiration in an ADP-activated oxidation of substrates (state 3). TPB(?), dose-dependently, shortened the lag time of MPP(+)-induced inhibition and thus lowered the concentrations of MPP(+) for the inhibition. However, TPB(?), even at the high concentration (10 ?M), did not significantly affect 4-PP-induced inhibition. Carbonyl-cyanide-m-chlorophenylhydrazone (CCCP) blocked the respiratory inhibition by MPP(+), independent of K(+) concentration in the medium, and valinomycin blocked the inhibition only in the medium containing high K(+) concentration. Determination of the intramitochondrial MPP(+) concentration revealed about 1000-fold concentrated MPP(+) from that in the medium during the incubation with TPB(?), indicative of potentiation of MPP(+) transport into mitochondria by TPB(?). This might account for the enhancement of respiratory inhibition by MPP(+). In the case of 4-PP, it will penetrate the mitochondrial membrane and intrinsically inhibit the respiration, but cannot accumulate in mitochondria. The present results indicate that, although the inhibitory potency of MPP(+)per se is similar to 4-PP, MPP(+) will be highly concentrated within mitochondria by the membrane potential, as the drive force for its transport.
Aiuchi
T
T
Laboratory of Biological Chemistry, School of Pharmaceutical Sciences Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142, Japan.
Shirane
Y
Y
Kinemuchi
H
H
Arai
Y
Y
Nakaya
K
K
Nakamura
Y
Y