Origin of selective inhibition of mitochondrial complex I by pyridinium-type inhibitor MP-24

Positively charged pyridiniums are unique inhibitors to probe the structura l and functional properties of the ubiquinone reduction site of bovine hear t mitochondrial complex I. In this study, we synthesized a series of neutra l as well as pyridinium analogues of MP-24 (N-methyl-4-[2-methyl-2-(p-tert- butylbenzyl)propyl]pyridinium), a selective inhibitor of one of the two pro posed binding sites of these pyridinium-type inhibitors of complex I (H. Mi yoshi et al., J. Biol. Chem. 273 (1998) 17368-17374), to elucidate the orig in of its selectivity. Inhibitory potencies of all neutral and pyridinium a nalogues with tetraphenylboron (TPB-), which forms an ion-pair with pyridin iums, were comparable, although the degrees of selective inhibition by pyri diniums without TPB- were entirely different. In contrast to MP-24, the dos e-response curves of nonselective pyridiniums and all neutral analogues wer e not affected by incubation conditions. These results strongly suggested t hat the process of the inhibitor passage to the binding sites is responsibl e for the selective inhibition. (C) 1999 Elsevier Science B.V. All rights r eserved.