Effect of MI‐D, a new mesoionic compound, on energy‐linked functions of rat liver mitochondria

Abstract

MI-D (4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride), a new mesoionic compound, depressed the phosphorylation efficiency of liver mitochondria as deduced from an accentuated decrease of the respiratory control coefficient and ADP/O ratio. Analysis of segments of the respiratory chain suggested that the MI-D inhibition site is further on than complex I and between complexes II and III. The transmembrane electrical potential (v vi i) was collapsed dependent on MI-D concentration. ATPase activity was dramatically increased by MI-D in intact mitochondria, but inhibited in carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled mitochondria. These results suggest that MI-D acts as an uncoupler agent, a property closely related to its structural characteristics.z 1998 Federation of European Biochemical Societies.

Interference of MI‐D, a new mesoionic compound, on artificial and native membranes

“…These results agree with those described by Cadena et al, 19 who considered MI-D to be an inhibitory uncoupler. Bearing in mind that such properties could restrain swelling in energized mitochondria and mask other effects on the membrane, intact mitochondria were used, where neither the respiratory chain nor the ATP synthase were functional due to the absence of substrates.…”

“…Thus, such pores could be formed in response to the presence of inhibitors of the electron transport chain. 38 Considering the known effects of MI-D, such as inhibition of electron transport, uncoupler action 19 and alterations in membrane permeability, as evidenced in the present research, these assumptions could explain the mechanism by which MI-D can induce tumour cell death, as described by Grynberg et al …”

“…Otherwise, the induction of swelling by MI-D in the presence of nigericin K would reinforce the proposition that MI-D is a new uncoupler agent as previously proposed. 19 In order to clarify the apparent perturbation induced by MI-D on membrane¯uidity, models consisting of DMPC liposomes were used in addition to those represented by native mitochondrial membranes. The probes DPH and DPH-PA whose localization in lipid bilayers is well known, 31,32 were chosen as tools to achieve information concerning the hydrophobic core and the outer regions of the bilayers respectively, taking into account that the¯uorescence polarization of their rotational movement is dependent on membrane¯uidity.…”

“…4±8 Effects such as potent anti-platelet, ®brinolytic, thrombolytic, broncholytic, 9,10 anticancer agents 11±13 or even on the cardiovascular system, 14±17 which are intimately related with the presence of speci®c substituent groups in the ring, 4,9,13 or related to the ability to release of nitric oxide 18 from the respective mesoionic structures, have pointed to their potential pharmaceutical use. Grynberg et al Studies from our laboratory 19 showed that MI-D was able to inhibit the respiratory chain between complexes II and III, collapse the transmembrane potential and stimulate ATPase activity in intact mitochondria. The important anti-tumoural effect of MI-D, 13 its actions on the energy-linked functions of isolated mitochondria and the suggestion that the internal mitochondrial membrane could be a primary target for the action of MI-D, 19 have motivated the present research.…”

“…Grynberg et al Studies from our laboratory 19 showed that MI-D was able to inhibit the respiratory chain between complexes II and III, collapse the transmembrane potential and stimulate ATPase activity in intact mitochondria. The important anti-tumoural effect of MI-D, 13 its actions on the energy-linked functions of isolated mitochondria and the suggestion that the internal mitochondrial membrane could be a primary target for the action of MI-D, 19 have motivated the present research. We now report the effects of MI-D on osmotic volume changes of liver mitochondria and on thē uidity of well-de®ned arti®cial model and native membranes by means of¯uorescence polarization of the probes 1,6-diphenylhexatriene (DPH) and 1,6-diphenylhexatriene-propionic acid (DPH-PA).…”