METAIODOBENZYLGUANIDINE INHIBITS COMPLEX-I AND COMPLEX-III OF THE RESPIRATORY-CHAIN IN THE HUMAN CELL-LINE MOLT-4

In this paper we report the effects of meta-iodobenzylguanidine (MIBG), a structural analogue of norepinephrine, on cell proliferation and several parameters related to mitochondrial respiration in Molt-4 cells. In micromolar concentrations, MIBG completely inhibited the proliferation of Molt-4 cells. In intact Molt-4 cells, a progressive increase in the lactate to pyruvate ratio was observed after incubation of these cells with glucose and increasing concentrations of MIBG. In Molt-4 cells permeabilized with digitonin, MIBG inhibited mitochondrial ATP synthesis when malate was used as a substrate. Succinate-driven synthesis of ATP was also inhibited by MIBG, although higher concentrations were required. These results indicate that apart from inhibition of complex I, MIBG inhibits at least one other complex of the respiratory chain. Measurement of the activities of the individual enzyme complexes in the presence of MIBG revealed that complex III is the other enzyme complex susceptible to inhibition by MIBG. Although maximal inhibition of ATP synthesis was observed at a concentration of 10 mu M, maximal inhibition of cell proliferation was observed at a concentration of 50 mu M of MIBG. This suggests that MIBG also influences other cellular processes apart from mitochondrial oxidative phosphorylation, resulting in additional inhibition of cell proliferation.