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PubMed1992

Butylated hydroxytoluene prevents cumene hydroperoxide-induced Ca2+ release from liver mitochondria by inhibiting pyridine nucleotide hydrolysis.

The mechanism by which the free radical scavenger butylated hydroxytoluene (BHT) prevents cumene hydroperoxide-induced Ca2+ release from rat liver mitochondria was studied. In Ca(2+)-loaded mitochondria cumene hydroperoxide induced a rapid oxidation and subsequent hydrolysis of the pyridine nucleotides. In the presence of BHT, pyridine nucleotide oxidation by cumene hydroperoxide occurred but was reversible as hydrolysis was prevented by BHT. However, the addition of BHT directly to rat liver submitochondrial particles did not inhibit NAD+ hydrolysis or the formation of ADP-ribose from NAD+. Thus, whilst BHT prevented NAD+ hydrolysis in isolated mitochondria, this appeared not to be due to a direct effect of BHT on the NADase. It is concluded that the mechanism of action of BHT on cumene hydroperoxide-induced Ca2+ release from mitochondria involves the inhibition of pyridine nucleotide hydrolysis by an indirect mechanism rather than the radical scavenging properties of BHT.

Adenosine Diphosphate Ribose↗
PubMed1982

The effects of some mitochondrial translocase inhibitors on the activity of rat liver transhydrogenase.

Non-energy dependent transhydrogenase activity in submitochondrial particles is stimulated at pH 8 by some inhibitors of mitochondrial carboxylate translocases. On solubilising the enzyme or assaying it at pH 6 these inhibitors have little effect. Km values remain unchanged under all these conditions. Conversely, energy-dependent transhydrogenase activity is inhibited by these substances possibly due to their direct action on proton transport. It is suggested that the observed effects may all be due to changes in membrane conformation induced by the inhibitors.

Adenosine Triphosphate↗
PubMed1984

Antimitochondrial effect of saturated medium chain length (C8-C13) dicarboxylic acids.

In isolated rat liver mitochondria, respiration was competitively inhibited by medium chain length (C8 to C13) dicarboxylic acids to different extents: the higher the number of carbon atoms up to C12, the greater the inhibition. In particular, experiments on submitochondrial particles showed that the competitive inhibition concerned the following enzymes: NADH dehydrogenase, succinic dehydrogenase and reduced ubiquinone: cytochrome c oxido-reductase. These results tend to confirm the suggestion that the melanocytotoxic effect of dicarboxylic acids, which are also competitive inhibitors of tyrosinase, may be primarily due to an antimitochondrial effect rather than being tyrosinase-dependent.

Adenosine Triphosphate↗
PubMed1984

Effects of gramine on energy metabolism of rat and bovine mitochondria.

The indole alkaloid gramine is found in several plant families. Its effects on mammalian mitochondria and submitochondrial particles were studied. Low concentrations of gramine slightly stimulated basal electron transport, totally inhibited the Ca2+-induced respiratory control and partially abolished the enhancement of 8-anilino-1-naphthalene sulfonate fluorescence induced by proton translocation coupled to ATP hydrolysis or to succinate oxidation. At higher concentrations gramine inhibited specifically the electron transport at the level of Complex I of the respiratory chain. The I50 values (2-6 mM) were dependent on the presence of uncouplers. Higher concentrations of the alkaloid also inhibited coupled succinate oxidation and ATP hydrolysis (I50 = 10 mM). Possible explanations for these effects are discussed.

Adenosine Triphosphate↗
PubMed1985

Inhibition of p-nitroanisole O-demethylation in perfused rat liver by oleate.

p-Nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats was rapidly and reversibly inhibited by sodium oleate (0.3 to 0.6 mM). Xylitol partially reversed this inhibitory effect. The inhibition was not mediated by a direct effect of oleate on microsomal components since concentrations of oleate ranging up to 1.0 mM did not affect p-nitroanisole O-demethylation by isolated microsomes. Infusion of 0.6 mM oleate did not alter the measured intracellular NAD+/NADH ratio but did cause a significant increase in the intracellular NADP+/NADPH ratio. A significant decrease in the ATP/ADP ratio was also observed. Oleoyl CoA inhibited p-nitroanisole O-demethylation in microsomes (Ki about 30 microM), and both oleoyl CoA and palmitoyl CoA inhibited the energy-linked nicotinamide nucleotide transhydrogenase in submitochondrial particles (Ki about 1 microM). Thus, inhibition of mixed-function oxidation in the intact liver by oleate is most likely mediated by oleoyl CoA. Oleoyl CoA inhibits mixed-function oxidation in the intact liver by acting directly on cytochrome P-450 and by decreasing generation of NADPH via inhibition of key enzymes of the citric acid cycle and the energy-linked transhydrogenase.

Acyl Coenzyme A↗
PubMed1985

Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin.

Mitochondrial degeneration is a consistently prominent morphological alteration associated with adriamycin toxicity which may be the consequence of adriamycin-enhanced peroxidative damage to unsaturated mitochondrial membrane lipids. Using isolated rat liver mitochondria as an in vitro model system to study the effects of the anticancer drug adriamycin on lipid peroxidation, we found that NADH-dependent mitochondrial peroxidation--measured by the 2-thiobarbituric acid method--was stimulated by adriamycin as much as 4-fold. Marker enzyme analysis indicated that the mitochondria were substantially free of contaminating microsomes (less than 5%). Lipid peroxidation in mitochondria incubated in KCl-Tris-HCl buffer (pH 7.4) under an oxygen atmosphere was optimal at 1-2 mg of mitochondrial protein/ml and with NADH at 2.5 mM. Malonaldehyde production was linear with time to beyond 60 min, and the maximum enhancement of peroxidation was observed with adriamycin at 50-100 microM. Interestingly, in contrast to its stimulatory effect on NADH-supported mitochondrial peroxidation, adriamycin markedly diminished ascorbate-promoted lipid peroxidation in mitochondria. Superoxide dismutase, catalase, 1,3-dimethylurea, reduced glutathione, alpha-tocopherol and EDTA added to incubation mixtures inhibited endogenous and adriamycin-augmented NADH-dependent peroxidation of mitochondrial lipids, indicating that multiple species of reactive oxygen (superoxide anion radical, hydrogen peroxide and hydroxyl radical) and possibly trace amounts of endogenous ferric iron participated in the peroxidation reactions. In submitochondrial particles freed of endogenous defenses against oxyradicals, lipid peroxidation was increased 7-fold by adriamycin. These observations suggest that some of the effects of adriamycin on mitochondrial morphology and biochemical function may be mediated by adriamycin-enhanced reactive oxygen-dependent mitochondrial lipid peroxidation.

Animals↗
PubMed1987

4-Chloro-4'-biphenylol as an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation.

4-Chloro-4'-biphenylol (4'-OH-4-CB), a metabolite of 4-chlorobiphenyl (4-CB), stimulated state 4 respiration and released oligomycin-inhibited state 3 respiration of rat liver mitochondria with succinate as the respiratory substrate. When glutamate/malate and beta-hydroxybutyrate were used as the substrates, however, 4'-OH-4-CB was ineffective on these parameters. This indicates that 4'-OH-4-CB uncouples oxidative phosphorylation with succinate, but not with glutamate/malate and beta-hydroxybutyrate. 4'-OH-4-CB severely inhibited 2,4-dinitrophenol (DNP)-stimulated respiration with glutamate/malate (ID50, 25 microM) and beta-hydroxybutyrate (ID50, 32 microM) because of the blockade of electron transfer between NADH and CoQ span, masking the uncoupling action of 4'-OH-4-CB. On the other hand, the inhibition of the respiration with succinate was only apparent at high 4'-OH-4-CB concentrations (ID50, 260 microM). 4'-OH-4-CB also inhibited the oxidation of NADH in submitochondrial particles (ID50, 35 microM). State 3 respiration was more intensely inhibited by 4'-OH-4-CB in the presence of either glutamate/malate (ID50, 23 microM) or beta-hydroxybutyrate (ID50, 26 microM) than that in the presence of succinate (ID50, 220 microM). Thus, 4'-OH-4-CB acts as both an uncoupler and an inhibitor of oxidative phosphorylation. The overall in vitro effect is to prevent ATP synthesis, which may be an important factor in the mechanism underlying the toxicity of 4-CB.

Adenosine Triphosphate↗
PubMed1988

Beneficial effects of trimetazidine on mitochondrial function and superoxide production in the cardiac muscle of monocrotaline-treated rats.

The administration of a single dose of monocrotaline (105 mg/kg) after 21 days produced in rats a reduction of cardiac mitochondrial function at the level of complexes I, II and IV of the respiratory chain, associated with the formation of heart hypertrophy, prevalently of the right ventricle. Moreover, in these rats, the submitochondrial particles produced more O2- and in the cardiac tissue there was an elevation of malondialdehyde content. The repeated administration of trimetazidine (5 mg/kg/24 hr) improved the cardiac mitochondrial function, particularly in state 3 of respiration. In addition, the treatment with trimetazidine reduced, in the heart muscle, both the production of mitochondrial O2- and the content of tissue malondialdehyde. Trimetazidine added alone did not significantly change either the cardiac mitochondrial activity, or the mitochondrial O2- production in comparison to control rats. Also, the content of tissue malondialdehyde was not modified by the repeated administration of trimetazidine. In all the experimental conditions examined, the content of cardiac water-soluble fluorescence substrates did not significantly change in comparison to control rats.

Animals↗
PubMed1990

Inhibition of cytochrome oxidase by dibucaine.

Dibucaine-HCl inhibited mitochondrial cytochrome c oxidase activity in intact mitochondria with 50% inhibition occurring at 1.1 mM dibucaine-HCl. Dibucaine-HCl did not prevent the reduction of cytochrome oxidase by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (TMPD) when measured at 604 nm but prevented 50% of the absorbance change at 445 nm; dithionite reduced the oxidase completely. Dibucaine prevented binding of CO to oxidase reduced with ascorbate plus TMPD by preventing the reduction of cytochrome a3. The midpotenials of cytochrome c and cytochrome oxidase, the visible absorbance wavelength maxima, and the position and intensity of the signals of the EPR spectrum of the oxidase were not affected. Dibucaine-HCl prevented ascorbate plus TMPD-driven reduction of the near infra-red detectable copper center associated with cytochrome a: dithionite subsequently reduced this center. Dibucaine-HCl inhibited cytochrome oxidase activity by interacting between cytochrome a and its associated copper. Since respiration was 8-fold less sensitive in submitochondrial particles, this site of inhibition is on the cytoplasmic side of the membrane.

Animals↗
PubMed1991

Inactivation of cytochrome c oxidase activity in mitochondrial membranes during redox cycling of doxorubicin.

Interactions of doxorubicin (DX) with the cardiolipin-dependent cytochrome c oxidase have been examined by using pig heart submitochondrial particles (SMP). A progressive and irreversible loss of oxidase activity is demonstrated in 2 hr incubations of the SMP with 10-100 microM DX in air-equilibrated medium with excess NADH to support redox-cycling of the drug. This oxidative mechanism for oxidase inactivation occurs in connection with a peroxidation process in the bulk membrane lipid, and is independent on turnover of the enzyme. It is related in a complex manner to the electron flux in the respiratory chain with antioxidant properties, and is maximal at the high reduction level of respiratory chain Complex I obtained in the presence of rotenone. Reduction of DX per se plays a minor role, and trace concentrations of chelatable metal ions (iron) are required to catalyse the reaction. Iron in the iron storage protein ferritin is released by DX, and at physiological low O2 concentrations ([O2] less than 20 microM), this iron is a better promoter of oxidase inactivation than is endogenous iron in the SMP. Kinetic analysis of inactivation data indicates the interaction of DX with low affinity (Km 35-55 microM) binding sites in the SMP membranes. Overall, the results point to the possible role of ferritin-iron in the mechanism of DX mitochondrial toxicity and argue against site specific effects of the DX-reduction/oxidation cycle on the cytochrome c oxidase or on its essential phospholipid (cardiolipin) environment.

Animals↗
PubMed1993

Inhibition of mitochondrial and Paracoccus denitrificans NADH-ubiquinone reductase by oxacarbocyanine dyes. A structure-activity study.

In this study, we determined that three structurally related oxacarbocyanine dyes, 3,3'-diethyloxacarbocyanine (DiOC2(3)), 3,3'-dipentyloxacarbocyanine (DiOC5(3)), and 3,3'-dihexyloxacarbocyanine (DiOC6(3)), and one oxadicarbocyanine, 3,3'-diethyloxadicarbocyanine (DiOC2(4)), inhibit bovine heart mitochondrial NADH oxidase activity and one of them, DiOC6(3), inhibits Paracoccus denitrificans NADH oxidase activity. The mitochondrial I50 values were 9 microM (DiOC2(3)), approximately 1 microM (DiOC5(3)) and DiOC6(3)), and approximately 3 microM (DiOC2(4)), whereas the I50 value for P. denitrificans was approximately 2 microM (DiOC6(3)). Neither succinate nor cytochrome oxidase (EC 1.9.3.1) activity was inhibited significantly by any of the compounds in either electron transport chain, localizing the inhibitory site of the oxacarbocyanine dyes to the respiratory chain segment between NADH and ubiquinone. With submitochondrial particles (SMP), NADH-dependent reduction of duroquinone and coenzyme Q1 was inhibited markedly by all four compounds with DiOC6(3) being the most potent inhibitor, and the reduction of menadione was inhibited substantially by DiOC6(3). When purified complex I was used, NADH-dependent reduction of ferricyanide was inhibited by DiOC5(3) and coenzyme Q1 reduction was inhibited by all oxacarbocyanines. With P. denitrificans membrane vesicles, DiOC6(3) substantially inhibited NADH-dependent reduction of coenzyme Q1. All the oxacarbocyanines were more effective inhibitors with membrane preparations than with complex I, suggesting that membrane interactions play a role in inhibition. The mechanism of inhibition of the oxacarbocyanines appears to be similar to that of rotenone since (a) essentially only electron acceptors affected by rotenone were affected by the compounds, (b) inhibition of menadione reduction was diminished drastically with rotenone-saturated SMP, and (c) inhibition of coenzyme Q1 was largely eliminated with rotenone-insensitive complex I, and P. denitrificans membrane vesicles.

Animals↗
PubMed1993

Cytotoxic effect of thiacarbocyanine dyes on human colon carcinoma cells and inhibition of bovine heart mitochondrial NADH-ubiquinone reductase activity via a rotenone-type mechanism by two of the dyes.

Five lipophilic-cationic thiacarbocyanine compounds differing in the side chains (methyl-S13, ethyl-S23, propyl-S33, butyl-S43, and pentyl-S53) and a related thiadicarbocyanine compound with ethyl side chains (S25) exhibited a selective cytotoxic effect on human colon carcinoma cells compared to green monkey kidney epithelial cells. The inhibitory concentration for 50% inhibition of growth (IC50) for the carcinoma cells ranged from 13 nM for S13 and S23 to 160 nM for S25. The carcinoma cells were 4- to 100-fold more sensitive than the normal cells. Two of the five compounds, S13 and S23, selectively inhibited NADH oxidase activity with bovine heart submitochondrial particles (SMP). There was no discernable inhibitory effect by the other three thiacarbocyanine compounds on electron transport chain activity. The primary site of inhibition within the respiratory chain for S13 and S23 appeared to be the NADH to coenzyme Q portion of the mitochondrial electron transport chain. Artificial electron acceptors for this segment of respiratory chain were used to localize the inhibitory site. Using SMP, both S13 and S23 inhibited reduction of menadione, duroquinone, and coenzyme Q. Using purified complex I (NADH-ubiquinone reductase) (EC 1.6.99.3), S13 slightly inhibited reduction of juglone, duroquinone, and coenzyme Q, whereas S23 had no effect on any of the substrates. When rotenone-saturated SMP were used, the inhibitory effects of S13, but not S23, on the reduction of menadione were abolished, as was the inhibitory effect of S13 on coenzyme Q reduction when rotenone-insensitive complex I was used as the source of the enzyme. These results suggest that (1) S13 and S23 inhibition of NADH-ubiquinone reductase activity is enhanced by the membrane environment of the enzyme, and (2) the inhibition appears to be in part akin to the inhibiting mode of rotenone.

Animals↗
PubMed1994

Effect of fluoxetine on rat liver mitochondria.

The in vitro and in vivo effects of fluoxetine (and its active metabolite norfluoxetine) on mitochondrial respiration and F0F1-ATPase were studied, respectively, in mitochondria and submitochondrial particles isolated from rat liver. Fluoxetine in vitro inhibited state 3 mitochondrial respiration for alpha-ketoglutarate and succinate oxidations (50% of effect at 0.25 and 0.35 mM drug concentrations, respectively); stimulated state 4 for succinate; and induced a decrease in the respiratory control ratio (RCR) for both oxidizable substrates. The F0F1-ATPase activity was determined at various pH levels in the absence and presence of Triton X-100. The solubilized form was not affected markedly, but an inhibition, apparently non-competitive, was observed for the membrane-bound enzyme, with 50% of the effect at a 0.06 mM drug concentration in pH 7.4. These results suggest that fluoxetine in vitro acts on F0F1-ATPase through direct interaction with the membrane F0 component (similar to oligomycin), or first with mitochondrial membrane and then affecting F0. A very similar behavior concerning the respiratory parameters and F0F1-ATPase properties was observed with norfluoxetine. The in vivo studies with fluoxetine showed stimulation of mitochondrial respiration in state 4 for alpha-ketoglutarate or succinate oxidations in acute or prolonged treatments (1 hr after a single i.p. dose of 20 mg of drug/kg of body weight, and 22 hr after 12 days of treatment with a daily dose of 10 mg/kg of body weight, respectively), indicating uncoupling of oxidative phosphorylation. Pronounced changes were not observed in the K0.5 values of F0F1-ATPase catalytic sites, but the Vmax decreased during the prolonged treatment. The results show that fluoxetine (as well as norfluoxetine) has multiple effects on the energy metabolism of rat liver mitochondria, being potentially toxic in high doses. The drug effects seem to be a consequence of the drug and/or metabolite solubilization in the inner membrane of the mitochondria.

Animals↗
PubMed1994

Mitochondrial respiratory activity and superoxide radical generation in the liver, brain and heart after chronic ethanol intake.

Functional characteristics of mitochondria isolated from liver, brain and heart were studied in ethanol-fed rats using ethanol administration in drinking water as a model of moderate alcohol intoxication. Our results show a slight decrease in liver cytochrome aa3 content, the mitochondrial alteration which is most consistently observed during chronic ethanol feeding. In liver and heart mitochondria, ethanol consumption led to an increase in state 3 respiration with NAD(+)-linked substrates, whereas no changes were apparent in respiration rates with succinate as substrate. However a decrease was found in state 3 respiration with succinate in brain mitochondria isolated from ethanol-fed rats. Submitochondrial particles (SMP) were used to study the superoxide radical (O2-.) production at the level of antimycin-inhibited regions of the respiratory chain. It appears that there is no clear correlation between ethanol effects on respiration and O2-. production. Whereas O2-. generation remained unchanged in heart mitochondria, an elevation of O2-. generation was observed in brain mitochondria, and in contrast, the rate of O2-. production was decreased in liver mitochondria of the ethanol-group in comparison to the control-group. Our findings support a tissue specificity for the toxic effects of ethanol towards the mitochondria and indicate that mitochondrial free radical mechanisms are involved in ethanol-induced toxicity in the brain.

Alcohol Drinking↗
PubMed1995

Carbocyanine dyes with long alkyl side-chains: broad spectrum inhibitors of mitochondrial electron transport chain activity.

Certain indocarbocyanine, thiacarbocyanine, and oxacarbocyanine dyes possessing short alkyl side-chains (one to five carbons) are potent inhibitors of mammalian mitochondrial NADH-ubiquinone reductase (EC 1.6.99.3) activity (Anderson et al., Biochem Pharmacol 41: 677-684, 1991; Anderson et al., Biochem Pharmacol 45: 691-696, 1993; Anderson et al., Biochem Pharmacol 45: 2115-2122, 1993), and act similarly to rotenone. This study examines the inhibitory capacities of twelve other carbocyanine dyes (six indocarbocyanines, four oxacarbocyanines, and two thiacarbocyanines) possessing long alkyl side-chains (seven to eighteen carbons with both saturated and unsaturated side-chains) on mitochondrial NADH, succinate and cytochrome c oxidase activities. Three of the indocarbocyanines inhibited electron transport chain activity, while three were non-inhibitory. Two of the oxacarbocyanines also inhibited electron transport chain activity, while the other two were without effect. Both the thiacarbocyanines were non-inhibitory. In contrast to previous studies, the long alkyl side-chain carbocyanines exhibited a broad spectrum of inhibition of respiratory chain activity, affecting either oxidation of all three substrates or of NADH and cytochrome c, rather than specific inhibition of mitochondrial NADH-ubiquinone reductase activity, indicating that there could be multiple binding sites for these compounds. The five inhibitory long side-chain carbocyanines also inhibited reduction of ferricyanide and coenzyme Q1 by NADH, using submitochondrial particles, but not when tested with purified complex I, indicating that the mitochondrial inner membrane was an integral component in their inhibitory capacity. No general correlation of side-chain length or degree of unsaturation and inhibitory capacity was discernible.

Animals↗
PubMed1995

The antianginal agent ranolazine is a weak inhibitor of the respiratory complex I, but with greater potency in broken or uncoupled than in coupled mitochondria.

Ranolazine (RS-43285) has shown antianginal effects in clinical trials and cardiac anti-ischaemic activity in several in vivo and in vitro animal models, but without affecting haemodynamics. Its mechanism is thought to mainly involve a switch in substrate utilisation from fatty acids to glucose to, thus, improve efficiency of O2 use; however, its precise molecular target(s) are unknown. In studies to investigate its action further, using isolated rat heart mitochondria, ranolazine was found to weakly inhibit (pIC50 values > 300 microM) respiration by coupled mitochondria provided with NAD(+)-linked substrates but not with succinate. With broken mitochondrial membranes or submitochondrial particles, ranolazine inhibited NADH but not succinate oxidation and with pIC50 values in the lower range of 3-50 microM. Studies with different electron acceptors and respiratory inhibitors indicated that it inhibits respiratory Complex I at a site between ferricyanide and menadione and ubiquinone-1 reduction (i.e. at a similar locus to rotenone). However, unlike rotenone, ranolazine was an uncompetitive inhibitor with respect to ubiquinone-1. Ranolazine inhibition of Complex I was reversible and occurred also with mitochondria from pig, guinea pig, and human heart, and rat liver. Further studies using rat heart mitochondria in different energisation states (i.e. broken, uncoupled, or coupled) showed a 50-100-fold shift to greater potency of ranolazine in the broken compared to the coupled; with the uncoupled it was about 2-fold less potent than the broken. These shifts in potency were not found with rotenone or amytal. Studies with radiolabelled ranolazine showed that it bound to mitochondrial membranes with greater affinity in the broken compared to the coupled or uncoupled conditions. Rotenone displaced radiolabelled ranolazine from its binding site. This property of ranolazine may play some role in its anti-ischaemic activity.

Acetanilides↗
PubMed1989

Litomosoides carinii: mode of action in vitro of benzothiazole and amoscanate derivatives with antifilarial activity.

It is suggested that the recently developed benzothiazole and amoscanate derivatives with antifilarial activity exert their action in vitro by an inhibition of mitochondrial-derived respiration. It was confirmed that the drugs CGP 20376, 21835, 20308, 21306, and 6140 cause a rapid immobilization in vitro of the adult filarial worm, Litomosoides carinii, the time required being similar to rotenone at the same concentration. The other drugs investigated, CGPs 20309, 21833, 24589, 23518, and 13231, were also effective; however, they required much longer incubation times. Submitochondrial particles (SMP) were prepared from Ascaris muscle and rat liver. The concentration of drug causing 50% inhibition of respiration (IC50) was calculated. It was found that the drugs most rapidly inhibiting respiration have IC50s for NADH oxidase of less than 25 microM in both Ascaris and rat liver SMP. This effect on SMP respiration could be overcome by using succinate as a substrate, indicating the site of inhibition to be within complex I of the mitochondrial respiratory chain. Further experiments showed that whereas the respiratory chain's NADH:ferricyanide reductase was unaffected by these drugs, there were pronounced effects on both Ascaris and rat liver NADH:quinone reductase activity. This suggests that the inhibition within complex I occurs after the flavoprotein dehydrogenase, but before the site of the quinone reduction. The other compounds examined, which had a slower effect on motility, also showed inhibition of the NADH oxidase, but not to as great an extent as the aforementioned compounds. The compounds most active against motility were also most effective at inhibiting respiration in intact adult L. carinii. Analysis of the aerobic end products produced by L. carinii showed that acetate production was greatly reduced even in the presence of low concentrations of the drugs. There was also a slight decrease in lactate production. However, a direct effect on the glycolytic pathway was ruled out by two observations. One, that the production of lactate from cell-free extracts of L. carinii is unaffected by the presence of the drugs, and secondly, that a protozoan, Giardia lamblia, reliant on glycolysis for energy production, can survive for long periods of time in the presence of high concentrations of the drugs. A correlation can be observed between the time for immobilization of the filarial worm and the strength of inhibition of mitochondrial respiration. Therefore, it is suggested that, at least in vitro, the mechanism of toxicity of these antifilarials in L. carinii is due to the blocking of the respiratory chain at a site similar to that of rotenone.

Anaerobiosis↗
PubMed1970

Uber die lokalisation eines energieunabhängigen K(+)-H(+)-austausches in der aussenmembran von rattenlebermitochondrien.

The energy-independent K(+)-H(+)-exchange was measured in intact mitochondria and submitochondrial particles at different K(+)-concentration of the incubation medium. Correlation was found between H+-displacement and specific activity of monoamine oxidase. It is concluded, that the energy-independent K(+)-H(+)-exchange is localized in the outer membrane of mitochondria.

Journal Article↗