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PubMed1998

Oxygen dependence of flux control of cytochrome c oxidase -- implications for mitochondrial diseases.

The oxygen dependence of cytochrome c oxidase control on succinate oxidation was investigated in saponin-permeabilized muscle fibers and isolated mitochondria from mouse quadriceps muscle applying metabolic control analysis. For this cyanide titrations of the oxygen consumption in the presence of succinate+rotenone were performed at different oxygen concentrations in the medium. While with isolated mitochondria high flux control coefficients were detected only at oxygen concentrations close to the KM value of cytochrome c oxidase, with saponin-permeabilized fibers a significant increase of cytochrome c oxidase flux control was already observed below 130 microM oxygen. The result is in line with the high oxygen sensitivity of maximal respiration of saponin-permeabilized muscle fibers (P50 = 33 microM) caused most probably by oxygen diffusion gradients through the fiber lattice. The oxygen dependence of cytochrome c oxidase flux control in muscle fibers can explain the pathological phenotype of mild cytochrome c oxidase deficiencies in mitochondrial myopathies.

Animals↗

PubMed1998

Protein phosphatase inhibitors and heat preconditioning prevent Hsp27 dephosphorylation, F-actin disruption and deterioration of morphology in ATP-depleted endothelial cells.

The vascular endothelium response to ischemic depletion of ATP was studied in vitro. Endothelial cells (EC) cultured from human aorta or umbilical vein were incubated in a glucose-free medium containing CCCP or rotenone. Such blockade of energy metabolism caused a drop in ATP, destruction of actin filaments, morphological changes, and eventually disintegration of EC monolayer within 2-2.5 h. While ATP fell and F-actin collapsed, the 27-kDa heat shock protein (Hsp27) lost basal phosphorylation and became Triton X-100-insoluble forming granules inside the cell nuclei. Protein phosphatase (PP) inhibitors (okadaic acid, cantharidin, sodium orthovanadate) did not delay the ATP decrease in energy-deprived EC but arrested both the alterations in the Hsp27 status and the changes for the worse in F-actin and cell morphology. Similarly, the Hsp27 dephosphorylation/insolubilization/granulation and the cytoskeletal and morphological disturbances resulting from lack of ATP were suppressed in heat-preconditioned (thermotolerant) cultures, this effect being sensitive to quercetin, a blocker of Hsp induction. The longer preservation of the cytosolic pool of phosphorylated Hsp27 during ATP depletion in the PP inhibitor-treated or thermotolerant EC correlated with the acquired resistance of F-actin and morphology. These data suggest that PP inhibitors as well as heat-inducible Hsp(s) can protect ischemia-stressed cells by preventing the ATP loss-provoked protein dephosphorylation and breakdown of the actin cytoskeleton.

Actins↗

PubMed1999

The participation of pyridine nucleotides redox state and reactive oxygen in the fatty acid-induced permeability transition in rat liver mitochondria.

The ability of low concentrations (5-15 microM) of long-chain fatty acids to open the permeability transition pore (PTP) in Ca(2+)-loaded mitochondria has been ascribed to their protonophoric effect mediated by mitochondrial anion carriers, as well as to a direct interaction with the pore assembly [M.R. Wieckowski and L. Wojtczak, FEBS Lett. 423 (1998) 339-342]. Here, we have compared the PTP opening ability of arachidonic acid (AA) with that of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) at concentrations that cause similar quantitative dissipation of the membrane potential (DeltaPsi) in Ca(2+)-loaded rat liver mitochondria respiring on succinate. The initial protonophoric effects of AA and FCCP were only slightly modified by carboxyatractyloside and were followed by PTP opening, as indicated by a second phase of DeltaPsi disruption sensitive to EGTA, ADP, dithiothreitol and cyclosporin A. This second phase of DeltaPsi dissipation could also be prevented by rotenone or NAD(P)H-linked substrates which decrease the pyridine nucleotide (PN) oxidation that follows the stimulation of oxygen consumption induced by AA or FCCP. These results suggest that, under the experimental conditions used here, the PTP opening induced by AA or FCCP was a consequence of PN oxidation. Exogenous catalase also inhibited both AA- and FCCP-induced PTP opening. These results indicate that a condition of oxidative stress associated with the oxidized state of PN underlies membrane protein thiol oxidation and PTP opening.

Animals↗

PubMed2003

The 9.8 kDa subunit of complex I, related to bacterial Na(+)-translocating NADH dehydrogenases, is required for enzyme assembly and function in Neurospora crassa.

A nuclear gene encoding a 9.8 kDa subunit of complex I, the homologue of mammalian MWFE protein, was identified in the genome of Neurospora crassa. The gene was cloned and inactivated in vivo by the generation of repeat-induced point mutations. Fungal mutant strains lacking the 9.8 kDa polypeptide were subsequently isolated. Analyses of mitochondrial proteins from mutant nuo9.8 indicate that the membrane and peripheral arms of complex I fail to assemble. Respiration of mutant mitochondria on matrix NADH is rotenone-insensitive, confirming that the 9.8 kDa protein is required for the assembly and activity of complex I. We found a similarity between the MWFE homologues and the C-terminal part of the nqrA subunit of bacterial Na(+)-translocating NADH:quinone oxidoreductases (Na(+)-NQR), suggesting a link between proton-pumping and sodium-pumping NADH dehydrogenases.

Amino Acid Sequence↗

PubMed2003

Prenylated isoflavonoids from Millettia pervilleana.

From the root bark of Millettia pervilleana, which had shown significant cytotoxic activity, a 3-phenylcoumarin, named pervilleanine, two new pterocarpans, pervilline and pervillinine, and one known, emoroidocarpan, were isolated in addition to rotenone and 3alpha-hydroxyrotenone. The anticancer activity of two previously isolated isoflavanones, pervilleanone and 3'-O-demethylpervilleanone is reported.

Antineoplastic Agents, Phytogenic↗

PubMed2003

Stimulation by surangin B of endogenous amino acid release from synaptosomes.

The effect of surangin B, an insecticidal natural product coumarin, on presynaptic release of endogenous amino acids was investigated using a purified synaptosomal fraction isolated from mouse brain. Surangin B stimulated the release of glutamic acid (GLU), gamma-aminobutyric acid (GABA), serine, alanine and the aminosulfonic acid taurine from synaptosomes at micromolar concentrations. In all cases, these responses were reduced by removing calcium from the saline and surangin B-evoked release of GLU, GABA, aspartic acid (ASP) and alanine was significantly inhibited by the sodium channel blocker tetrodotoxin. Rotenone (a complex I inhibitor) and carbonyl cyanide chlorophenylhydrazone (CCCP; an uncoupler), were more potent releasers of amino acids from synaptosomes than surangin B, however, carboxin (a complex II-selective inhibitor), was extremely weak to ineffective in this regard. The stimulatory effect of surangin B and complex III-selective inhibitors on release of GLU, GABA, ASP and alanine by synaptosomes was significantly reduced by N,N,N',N'-tetramethyl-p-phenylenediamine, suggesting that blockade of complex III in intraterminal mitochondria is an important effect of this coumarin. Our results demonstrate that surangin B, in common with CCCP and inhibitors of complex I and III, cause release of both neurotransmitter and non-neurotransmitter amino acids from nerve endings in vitro. However, in contrast to most classical agents which interfere selectively with mitochondrial function, the release of endogenous amino acids from synaptosomes by surangin B also involves a moderate extracellular calcium ion-dependent component and relies partially on sodium ion entry into the nerve ending.

Alanine↗

PubMed1997

Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON).

The complex I function in sub-mitochondrial particles was studied in platelets from patients and healthy carriers with 11778/ND4 or 3460/ND1 mtDNA point mutations associated with LHON. Both 11778/ND4 and 3460/ND1 mutations induced rotenone resistance and 11778/ND4 showed an increased K(m) for ubiquinol-2 with respect to the control group. It was concluded that even with different pathogenic mechanisms both mutations affect the quinone binding site of complex I.

Binding Sites↗

PubMed1996

Sphingosine-induced inhibition of capacitative calcium influx in CFPAC-1 cells.

Sphingosine (10 microM) induced mobilization of intracellular Ca2+ stores in the pancreatic duct adenocarcinoma cell line CFPAC-1. The effect was specific for sphingosine, since the sphingosine analog C2-ceramide had no effect. Sphingosine did not cause Ca2+ entry from extracellular medium, as also shown by following Mn2+ quenching of Fura-2 fluorescence. Furthermore, sphingosine, similarly to the mitochondrial inhibitors rotenone and oligomycin, strongly inhibited the rate of Mn2+ entry triggered by both thapsigargin- and agonist-induced depletion of intracellular stores. The uptake of rhodamine 123, a lipophilic cation which estimates mitochondrial energy level, was reduced by sphingosine to an extent similar to that observed in the presence of mitochondrial inhibitors. It is suggested that impairment of mitochondrial function might be responsible for inhibition of capacitative Ca2+ entry caused by sphingosine.

Adenocarcinoma↗

PubMed1996

Regulation of intracellular calcium is closely linked to glucose metabolism in J774 macrophages.

The effects of 2-deoxy-D-glucose (2dGlc) and glucose deprivation were investigated in the J774 murine macrophage-like cell line. 2dGlc addition or glucose deprivation for 4 min led to an inhibition in the transient increase in cytoplasmic free Ca2+ ([Ca2+]i) that otherwise occurs in response to three different agonists: IgG, ATP and platelet activating factor. This inhibition was preceded by a partial release of Ca2+ from intracellular, thapsigargin-sensitive stores. In contrast, the transition from 5 to 30 mM glucose caused a decrease in [Ca2+]i and a corresponding increase in thapsigargin-sensitive sequestered Ca2+. The effects of an alternate glycolytic inhibitor, NaF, and a mitochondrial inhibitor, rotenone, were also tested. These inhibitors caused neither a release of Ca2+ from intracellular stores nor an inhibition in any of the agonist responses. The capacitative influx of extracellular Ca2+ following depletion of intracellular stores was also found to be selectively inhibited by the prior addition of 2dGlc or with glucose deprivation. In addition, when an elevated plateau of [Ca2+]i was established by the irreversible depletion of intracellular Ca2+ stores, the addition of 2dGlc caused a decrease in the on-going capacitative entry of Ca2+.

Adenosine Triphosphate↗

PubMed2002

The respiratory chain complex thresholds in mitochondria of a Drosophila subobscura mutant strain.

Analysis of a mutant strain of Drosophila subobscura revealed that most (80%) mitochondrial genomes have undergone a large scale deletion (5 kb) in the coding region. Compared with the wild-type strain, complex I and III activities are, respectively, reduced by 50% and 30% in the mutant. However, the ATP synthesis capacities remain unchanged. In order to elucidate how the ATP synthesis is maintained at a normal level, despite a significant decrease in complex I and III activities, we progressively inhibited respiratory chain complex activities, respiration rate and ATP synthesis. Complex I, III and IV activities were inhibited by rotenone, antimycin and KCN, respectively. Threshold curves were thus determined for each complex. Our results demonstrated that in the mutant strain, both mitochondrial respiration and ATP synthesis had decreased when complex I activity was inhibited by more than 20%, whereas 70% inhibition is required to induce similar changes in the wild-type. The complex I inhibition pattern of the wild-type was restored by a backcross (mutant female/wild-type male). The complex III activity threshold is below 20% in both strains, and we observed some difference in antimycin sensitivity, suggesting a modification of the complex enzymatic properties in the mutant. In contrast, threshold values of 70% were measured for complex IV inhibition. Our data suggest that the difference in the complex I threshold curves between the wild-type and mutant strains could partially account for the absence of pathological phenotype in the mutant.

Adenosine Triphosphate↗

PubMed1975

Effects of catecholamines on rat myocardial metabolism. II. Influence of catecholamines on 32p-incorporation into rat myocardial adenylic nucleotides and their turn-over.

1. The influence of catecholamines (adrenaline and noradrenaline) on 32Pi incorporation into intracellular phosphate and adenylic nucleotides has been studied on rat myocardium slices; consequently, the turn-over of nucleotides could be determined and compared under the influence of these two hormones. 2. In order to specify the site of action of these catecholamines, several inhibitors and activators of energetic metabolism were included in the incubation medium: 3'5'-AMP, caffein, ouabain, oligomycin, rotenone + antimycin. 3. Both catecholamines favour Pi exchanges between intra and extracellular spaces; ATP turn-over is greatly increased, while ADP turn-over is slightly decreased, and 32P-incorporation into ADP is increased. 4. 3'5'-AMP and caffein are without effect on Pi penetration; however, caffein increases catecholamine effects on this penetration. ATP turn-over is slightly increased by 3'5'-AMP or caffein. 5. Ouabain decreases ATP turn-over but does not prevent the adrenaline induced acceleration. Inhibitors of oxidative phosphorylation and electron transport decrease ATP-turn-over severely; this inhibition is not released by catecholamines. 6. It is concluded that the catecholamine effects observed are dependent on the oxidative phosphorylations process. The increase of Pi exchange by catecholamines may be related to the increase of extracellular space and cation translocations we observed with the hormones.

Adenine Nucleotides↗

PubMed1985

The function of redox shuttles during aerobic glycolysis in two strains of Ehrlich ascites tumor cells.

The function of glycerophosphate and malate-aspartate shuttles during glucose metabolism in two strains of Ehrlich ascites tumor cells was evaluated by several experimental approaches. The activities of the enzymes involved in these shuttle systems were assayed in the cytosolic and mitochondrial compartments after cell fractionation by the digitonin method. The glycerophosphate shuttle can be ruled out because of the lack of relevant enzymatic activities, and the failure of glucose to increase rotenone-inhibited respiration. Analysis of glycolytic flux in the presence of aminooxyacetate indicates that the activity of malate-aspartate shuttle may be very low. Balance studies of glucose uptake and lactate production suggest the existence of other pathways for the reoxidation of cytosolic NADH, which are acetyl-CoA dependent. Estimation of citrate synthase and ATP citrate lyase, in addition to the observed high activity of malate dehydrogenase, suggests a malate-citrate shuttle.

Aerobiosis↗

PubMed2002

ATP-independent anoxic activation of ATP-sensitive K+ channels in dorsal vagal neurons of juvenile mice in situ.

The role of ATP in anoxic activation of ATP-sensitive K+ (KATP) channels was studied in dorsal vagal neurons of mouse brainstem slices. In the whole-cell configuration, cyanide-induced chemical anoxia evoked within 10 s a 300-pA outward current that gave rise to a hyperpolarization of 24 mV. These responses were mimicked by nitrogen-aerated saline, rotenone or diazoxide and abolished by tolbutamide. The cyanide-induced hyperpolarization was due to activation of 70 pS K(ATP) channels that were half-maximally blocked by 5 microM internal ATP. Dialyzing the cells with either 1, 20 or 0 mM ATP did not, however, affect the time to onset, the kinetics or the magnitude of the cyanide-induced hyperpolarization. Impairment of ATP consumption by ouabain, vanadate or reduced temperature had no effect either. Thus, anoxia-induced activation of these KATP channels cannot be explained by a fall of cellular ATP or a concomitant rise of ADP. Anoxia-related changes of the actin cytoskeleton or the composition of the plasma membrane are also not likely to be involved, as cytochalasin D did not affect the cyanide-evoked hyperpolarization and phosphatidylinositol 4,5-bisphosphate failed to decrease the ATP sensitivity of single KATP channels. Finally, because of a lack of effects of reduced/oxidized glutathione and the oxidase blocker diphenyliodonium on the cyanide-induced hyperpolarization, cellular redox state does not appear to be involved. Our results indicate that despite a high sensitivity to ATP in excised patches, anoxic activation of KATP channels is independent of cellular ATP. Rather the ATP block seems to be removed as a consequence of impaired mitochondrial function.

Actin Cytoskeleton↗

PubMed2003

Characterization of plasma membrane respiratory chain and ATPase in the actinomycete Nonomuraea sp. ATCC 39727.

We have characterized the respiratory system of the aerobic actinomycete Nonomuraea sp. ATCC 39727. The plasma membrane of the microorganism is shown to contain a protonmotive respiratory chain and H+-ATPase. The respiratory chain is made up of a rotenone-sensitive NADH-quinone oxidoreductase, a four subunits aa3-type cytochrome c oxidase and a bc1 complex. The H+-ATPase is characterized as an F0F1-type on the basis of its sensitivity to specific inhibitors; the enzyme is also inhibited by mM concentrations of Ca2+. The activity of the respiratory chain increases during the exponential growth phase, but is depressed in the stationary phase. The H+-ATPase activity reaches, as the respiratory chain, a maximal activity at the end of the exponential growth phase and then remains constant in the stationary phase.

Actinomycetales↗

PubMed2000

Effect of Tephrosia vogelii and Justicia extensa on Tilapia nilotica in vivo.

According to our and other ethnobotanic studies (Walker, R., 1951. Une Nouvelle Légumineuse du Gabon servant à narcotiser le poisson. Rev. Bot. Appl. 31, 327; Walker, R., Sillans, R., 1961. Les plantes utiles du Gabon. Encyclopédie Biologique. P. Chevalier, Paris; Halle, N., 1970. Flore du Gabon 17, Famille des Rubiacées. Museum National d'Histoire Naturelle, Paris; Mounzeo, H., et al., 1997. Quelques plantes utilisées comme poisons de pêches chez les Punu du Gabon. Le Flamboyant 44. Décembre, Bulletin de Liaison des membres du réseau 'Arbres Tropicaux'), Tephrosia vogelii and Justicia extensa are two plants whose leaves are particularly used for the catching of fish in Gabonese rivers. The leaf extracts of those plants have been tested on Tilapia nilotica in order to observe their toxicity. At a given dose, the small fish are the first to be poisoned. This toxicity is more important for J. extensa and increased in a dose-dependent manner. After boiling for 90 min, those leaf extracts and rotenone (10(-6) M) taken as a control retain their toxicity at high dose (625 mg/l), although the latency period is higher. With the same temperature condition, at weak doses (37.5 and 62.5 mg/l), T. vogelii loses its toxicity, whereas J. extensa preserves it at 62.5 mg/l. As shown in our results, the fact that the extracts preserve their toxicity at high dose after boiling requires particular attention be given to the doses used for fishing and to the type of plants used.

Animals↗

PubMed1998

Childhood Leber's hereditary optic neuropathy (ND1/3460) with visual recovery.

The authors report the clinical features and the results of genetic and biochemical studies of a child affected by ND1/3460 Leber's hereditary optic neuropathy, who demonstrates a persistent visual recovery after protracted monitoring. A 10-year-old male suffered from a severe right visual impairment that was incidentally detected. Within 2 months the left eye was also seriously involved, and visual acuity worsened to 20/300 in both eyes, associated with bilateral cecocentral scotomas and dyschromatopsia. During the following months a progressive visual improvement occurred, and 2 years later the visual acuity was 20/20 OU. After 9 years of follow-up the clinical status is unchanged. The mutation at np ND1/3460 was found to be virtually homoplasmic in the proband's mtDNA, which was extracted either from platelets or leukocytes, whereas the mother and the sister tested heteroplasmic for the same mutation. The specific activity of complex I in platelets was reduced in the proband and normal in his relatives. An abnormal resistance of NADH:ubiquinone reductase to the inhibitory effect of rotenone was found in platelet mitochondria from the proband and family members and was consistent with the degree of heteroplasmy. This pattern of biochemical abnormalities suggests a cumulative effect of the increasing percentage of mutated mtDNA on complex I function, which involves the interaction between complex I and its substrate ubiquinone in the heteroplasmic condition (asymptomatic state), and the catalytic function of complex I, as mutated mDNA turns toward the homoplasmic condition (symptomatic state).

Blood Platelets↗

PubMed2001

Dynamics of intracellular calcium and free radical production during ischemia in pyramidal neurons.

Biochemical cascades initiated by oxidative stress and excitotoxic intracellular calcium rises are thought to converge on mitochondrial dysfunction. We investigated the contribution of mitochondrial dysfunction to free radical (FR) overproduction in rat CA1 pyramidal neurons of organotypic slices subjected to a hypoxic-hypoglycemic insult. Ischemia-induced FR generation was decreased by the mitochondrial complex I blocker, rotenone, indicating that mitochondria are the principal source of ischemic FR production. Measurements of mitochondrial calcium with the mitochondrial calcium probe dihydroRhod-2, revealed that FR production during and after the anoxic episode correlates with the accumulation of mitochondrial calcium. However, the mitochondrial calcium uptake inhibitor Ru360 did not prevent FR generation during ischemia and attenuated it to some degree during reoxygenation. On the other hand, the mitochondrial permeability transition blocker cyclosporinA (CsA) completely arrested both ischemic FR generation and mitochondrial calcium overload, and prevented deterioration of neuronal intrinsic membrane properties. CsA had no effect on the accumulation of intracellular calcium during ischemia-reperfusion. Nicotinamide, a blocker of NAD+ hydrolysis, reproduced the CsA effects on FR generation, mitochondrial calcium accumulation and cytoplasmic calcium increases. These observations suggest that a major determinant of ischemic FR generation in pyramidal neurons is the uncoupling of the mitochondrial respiratory chain, which may be associated with the mitochondrial permeability transition.

Aniline Compounds↗

PubMed2003

External alternative NADH dehydrogenase of Saccharomyces cerevisiae: a potential source of superoxide.

Three rotenone-insensitive NADH dehydrogenases are present in the mitochondria of yeast Saccharomyces cerevisiae, which lack complex I. To elucidate the functions of these enzymes, superoxide production was determined in yeast mitochondria. The low levels of hydrogen peroxide (0.10 to 0.18 nmol/min/mg) produced in mitochondria incubated with succinate, malate, or NADH were stimulated 9-fold by antimycin A. Myxothiazol and stigmatellin blocked completely hydrogen peroxide formation with succinate or malate, indicating that the cytochrome bc(1) complex is the source of superoxide; however, these inhibitors only inhibited 46% hydrogen peroxide formation with NADH as substrate. Diphenyliodonium inhibited hydrogen peroxide formation (with NADH as substrate) by 64%. Superoxide formation, determined by EPR and acetylated cytochrome c reduction in mitochondria was stimulated by antimycin A, and partially inhibited by myxothiazol and stigmatellin. Proteinase K digestion of mitoplasts reduced 95% NADH dehydrogenase activity with a similar inhibition of superoxide production. Mild detergent treatment of the proteinase-treated mitoplasts resulted in an increase in NADH dehydrogenase activity due to the oxidation of exogenous NADH by the internal NADH dehydrogenase; however, little increase in superoxide production was observed. These results suggest that the external NADH dehydrogenase is a potential source of superoxide in S. cerevisiae mitochondria.

Antifungal Agents↗