Selective inhibition of complex I by N-methylisoquinolinium ion and N-methyl-1,2,3,4-tetrahydroisoquinoline in isolated mitochondria prepared from mouse brain

1,2,3,4-Tetrahydroisoquinoline (TIQ), which is structurally similar to MPTP, has been found in human brain and has been reported to inhibit the mitochondrial respiration as does 1-methyl-4-phenylpyridinium ion (MPP + ). However, the potency of inhibition by TIQ is less than that of MPP + . In this study, we report the effects of N -methyl-1,2,3,4-tetrahydroisoquinoline ( N -Me-TIQ) and N -methylisoquinolinium ion ( N -Me-IQ + ) on the mitochondrial electron transport system using mitochondria prepared from mouse brains. Five mM N -Me-TIQ and 500 μ M N -Me-IQ + inhibited complex I activity to 54% and 63% of the control, respectively. The IC 50 of N -Me-TIQ and N -Me-IQ + were approximately 6.5 mM and 650 μM, respectively. Neither substance inhibited complex II, III and IV activities. Kinetic analyses of N -Me-IQ + on complex I activity revealed uncompetitive inhibition against NADH and non-competitive inhibition against ubiquinone. These inhibitory characteristics were the same to those of MPP + and the inhibitory potency of N -Me-IQ + on complex I activity was stronger than that of MPP + .