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At least 1,423 records · Page 79Linked to original sources
PubMed1995

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I.

The neurotoxic agent MPP+ is an artificial substance producing a syndrome very similar to that of idiopathic Parkinson's disease. There are also naturally occuring neurotoxic substances under discussion like the group of isoquinoline and beta-carboline alkaloids. All these substances are more or less powerfull inhibitors of complex I of the mitochondrial oxidative phosphorylation. This study examined the effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a putative in vivo condensation product of chloralhydrate and tryptamine, on the oxidative phosphorylation system compared to MPP+. Similar to MPP+, TaClo inhibits only the electron transfer from complex I towards ubiquinone. Demonstrating a 10-times more effective inhibition than MPP+, complex I activity is fully inhibited by 800 microM TaClo in brain homogenates and submitochondrial particles. By extending the preincubation time from 5 to 30 min complex I is already inhibited by 400 microM TaClo. Other derivates of TaClo as N-methyl-TaClo demonstrate an even greater inhibitory effect on complex I and especially on complex II activities.

1-Methyl-4-phenylpyridinium↗
PubMedDate not supplied

The effect of dithiocarbamates on neurotoxic action of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on mitochondrial respiration chain.

The neurotoxin MPTP induces in human and in some laboratory animals parkinsonism-like neurological disorder, biochemically characterized by selective and irreversible decrease of dopamine content in striatum. The terminal step in the mechanism of neurotoxic action of MPTP is the inhibition of mitochondrial respiratory chain by pyridinium metabolite (MPP+) resulting in energy depletion and nervous cells death. Earlier it was shown that some chemical compounds, in particular diethyldithiocarbamate (DTC), can potentiate MPTP neurotoxicity. In the present work we have studied the influence of DTC derivatives on MPTP neurotoxic effect in vivo and on MPP+ inhibition of mitochondrial respiration (both on intact mitochondria and on submitochondrial particles) in vitro. It was revealed that DTC alone change mitochondrial membrane state by respiratory chain uncoupling and inhibition. DTC and MPP+ mutually potentiate inhibition of electron transport as well. The combined effect of DTC plus MPP+ action on mitochondria respiration reflects the sum of reciprocally leveling and potentiating factors and can explain the order of efficacy of MPTP-neurotoxicity potentiation in vivo in series of close DTC derivatives.

Animals↗
PubMed1997

The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I.

The synthetic pyrethroid derivatives permethrin and cyhalothrin are widely used insecticides that are considered to be relatively nontoxic to higher animals. However, a variety of toxic effects on mammals have been reported. We investigated the effect of these drugs on energy coupling by mitochondria and on the activity of the individual respiratory complexes. Using isolated rat liver mitochondria, a concentration-dependent inhibition of glutamate and succinate sustained state 3 respiration was found for both compounds in the micromolar range. The effect of pyrethroids on the activities of the complexes I to V were assessed individually in submitochondrial particles (complex I) and in freeze-thawed mitochondria (complexes II-V). Complex I (EC 1.6.5.3) was found to be the most sensitive link within the electron transport chain. Half-maximal inhibition was observed at 0.73 microM permethrin and 0.57 microM cyhalothrin, respectively, and exhibited sigmoidal inhibition kinetics. Complexes II, III, IV and V (EC 1.3.5.1, 1.10.2.2, 1.9.3.1, 3.6.1.34) were not significantly inhibited by up to 50 microM of these drugs. Thus, our results reveal a model of action of synthetic pyrethroid insecticides not previously reported.

Animals↗
PubMed1982

Cholesterol as activator of ADP-ATP exchange in reconstituted liposomes and in mitochondria.

The influence of cholesterol on ADP-ATP exchange activity was measured in the reconstituted system, submitochondrial (sonic) particles and mitoplasts (isolated inner mitochondrial membranes). In the reconstituted system, cholesterol markedly enhanced the nucleotide-uptake rate, when added to membranes of various compositions i.e., pure phosphatidylcholine, phosphatidylcholine/phosphatidylethanolamine mixtures and crude egg yolk phospholipids. The stimulation was linearly dependent on the amount of incorporated cholesterol up to 7-13% added sterol, depending on the type of phospholipids. Cholesterol influenced neither the amount of actively reconstituted carrier proteins nor the affinity of the carrier towards nucleotides nor the breakpoint of temperature dependence in the Arrhenius plot. The stimulation could be correlated with an increase in the molecular activity of the carrier protein. The influence of cholesterol was also measured in the natural environment of the carrier protein, i.e., the inner mitochondrial membrane. Both with submitochondrial particles from beef heart and especially with mitoplasts from rat liver, incorporation of cholesterol by fusion with sterol-containing liposomes led to a stimulation of ADP-ATP exchange activity, comparable to the effect in the reconstituted system. These results are discussed in relation to the absence of cholesterol in the inner mitochondrial membrane and in the view of the generally accepted ordering effect of cholesterol on phospholipid bilayers.

Animals↗
PubMed2006

Mutagenicity of diesel exhaust particles mediated by cell-particle interaction in mammalian cells.

Diesel exhaust particle (DEP) has been identified as a class 2A human carcinogen and closely related to the increased incidence of respiratory allergy, cardiopulmonary morbidity and mortality, and risk of lung cancer. However, the molecular mechanisms of DEP mutagenicity/carcinogenicity are still largely unknown. In the present study, we focused on the mutagenicity of DEPs in human-hamster hybrid (A(L)) cells and evaluated the role of cell-particle interaction in mediating mutagenic process. We found that DEPs formed micron-sized aggregates in the medium and located mainly in large cytoplasmic vacuoles of cells by 24h treatment. The cellular granularity was increased by DEP treatment in a dose-dependent manner. DEPs resulted in a dose-dependent increase of mutation yield at CD59 locus in A(L) cells, while inflicting minimal cytotoxicity. There was a more than two-fold increase of mutation yield at CD59 locus in A(L) cells exposed to DEPs at a dose of 50mug/ml. Such induction was significantly reduced by concurrent treatment with phagocytosis inhibitors, cytochalasin B and ammonium chloride (p<0.05). These results provided direct evidence that DEPs was mutagenic in mammalian cells and that cell-particle interaction played an essential role in the process.

Ammonium Chloride↗
PubMed1987

Does the energy state of mitochondria influence the surface potential of the inner mitochondrial membrane? A critical appraisal.

Binding of 8-anilino-1-naphthalene sulphonate (ANS) to rat liver mitochondria and submitochondrial inside-out particles was measured under energized and de-energized conditions. In mitochondria, energization/de-energization changed the binding capacity for ANS extrapolated for its infinitely high concentration, whereas the apparent Kd value remained unchanged. In submitochondrial particles apparent Kd was changed but the extrapolated maximum binding was not altered. These results are compatible with theoretical considerations assuming a free permeability of mitochondrial membranes to ANS and its distribution according to the transmembrane potential. The spin-labelled cationic amphiphile, 4-(dodecyl dimethyl ammonium)-1-oxyl-2,2,6,6-tetramethyl piperidine bromide (CAT12), was trapped by de-energized mitochondria in such a way that about half of the bound probe became inaccessible to reduction by externally added ascorbate. This inaccessible fraction was increased by energization. This indicates that this cationic probe can penetrate through the inner mitochondrial membrane. De-energization produced a parallel shift of the Lineweaver-Burk plots for the oxidation of external ferrocytochrome c by mitoplasts and of succinate by submitochondrial particles. A similar shift was obtained by a partial inhibition of succinate oxidation by antimycin A. Thus, the observed changes of the kinetics of the two membrane-bound enzyme systems on de-energization can be interpreted as reflecting changes of the control points of mitochondrial respiration rather than changes of the surface potential. It is concluded that neither the fluorescent probe ANS, the spin-labelled amphiphilic cation CAT12, nor the kinetics of some respiratory enzyme systems provide a sufficient proof for changes of the surface potential of the inner mitochondrial membrane upon energization.

Anilino Naphthalenesulfonates↗
PubMed1990

Vitamin E radical reaction with antioxidants in rat liver membranes.

The Japanese herbal medicine Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960) has been demonstrated to have an antioxidant action by quenching free radicals. The effects of TJ-960 on the tocopheroxy radicals generated by an arachidonic acid and lipoxygenase oxidation system were compared with those of the ascorbate and glutathione in vitamin E-enriched rat liver microsomes and submitochondrial membrane particles (SMP). Using electron spin resonance spectrometry, the disappearance of the tocopheroxy radicals after addition of glutathione and ascorbate was detected in microsomes and SMP, with ascorbate displaying a more potent action than glutathione. Addition of TJ-960 demonstrated a similar effect on the tocopheroxy radicals in microsomes and SMP. In the presence of TJ-960, ascorbate, and glutathione, the loss of vitamin E in the vitamin E-enriched microsomes of rat liver undergoing oxidation was slowed down. In this paper, we introduced TJ-960 as another replenisher of vitamin E in membrane, increasing the membrane's resistance against oxidative damage.

Animals↗
PubMedDate not supplied

Microprocessor controlled particle counter system.

Operation of an optical particle counter with microprocessor control of particle size calibration and data recording is described. Sensors are available to measure particles 0.1 micron and larger. A system with a range from 2 microns to 125 microns will be described. Calibration data based on response to monosized particles are stored in the system memory, along with sensor resolution information and system changes since the last calibration. The instrument adjusts the particle size channels internally for the selected calibration base particles. Once calibrated, the instrument can be set to report data in operator selectable sizes or any of four default particle size groups. Three default groups are based on pharmaceutical and hydraulic fluid power industry standards and one is set in a logarithmic spread of 16 particle sizes that covers the system dynamic range. A front-panel keyboard and CRT display allow selection and control of all operating parameters. These include reported size ranges, liquid sample size, number of sample replications (including suspect sample rejection), data averaging, and comparison of data from two sensors. Differential or cumulative data can be reported in tabular or histogram format. Data can be sent to an internal thermal printer or to an RS-232C output.

Calibration↗
PubMed1998

Continuous free-flow electrophoresis.

This review evaluates the literature on continuous free flow electrophoresis, published during the last four years. Its aim is to serve not only experts in the field but also newcomers, and, therefore, it also briefly describes the principles of the method and the techniques used, referring to fundamental papers published earlier. The actual commercial instrumentation is briefly outlined. A substantial part of this review is devoted to the optimization of the performance of this method. Finally, diverse applications of fractionations of charged species in solution, ranging from small ions to biological particles and cells, are surveyed.

Animals↗
PubMed1997

Association of transcripts from a group-I intron-containing gene with high sedimentation coefficient particles.

The mitochondrial gene coding for the large rRNA contains a self-splicing optional group-I intron (Sc-LSU.1) in some Saccharomyces cerevisiae strains. Although the mechanisms of splicing have been extensively studied, little is known about the possible interactions of this intron with other mitochondrial molecules such as proteins. Using glycerol gradients, we have compared the sedimentation coefficients of mitochondrial transcripts containing the Sc-LSU.1 intron in native yeast extracts and in purified RNA preparations. By comparing extracts from rho+ and rho- cells we have found that at least three RNA species containing the Sc-LSU.1 intron (4.5 kb, 2.7 kb and 1.2 kb respectively) are associated in vivo with a multimolecular complex of sedimentation coefficient 50S made up of nuclearly encoded proteins. Another RNA species of 2.7 kb, which may correspond to a cleavage at the dodecamer sequence of the intron, is not associated with the same particle. The possibility that the 50S particle corresponds to the mitochondrial ribosome or its precursor form(s) is discussed.

Centrifugation, Density Gradient↗
PubMed1981

A comparison of the phosphorylation potential and electrochemical proton gradient in mung bean mitochondria and phosphorylating sub-mitochondrial particles.

The phosphorylation potential (delta Gp) and the electrochemical proton gradient (delta muH+) normally maintained during respiration or ATP hydrolysis by mung bean hypocotyl mitochondria and phosphorylating sub-mitochondrial particles have been investigated. Phosphorylation potential experiments using safranine and oxonol-VI, as membrane potential markers for mitochondria and sub-mitochondrial particles, respectively, suggest that the 'null point' delta Gp (i.e., the phosphorylation potential at which no change in optical signal occurred) corresponds to a value of 15.2 +/- 0.7 kcal/mol in mitochondria and 11.2 +/- 0.3 kcal/mol in sub-mitochondrial particles. The value of delta muH+ generated by the hydrolysis of ATP was estimated using ion distribution techniques. In each case a rapid centrifugation technique was used to separate the organelle from the suspending medium. The total delta muH+ generated in each case was approx. 200 mV being composed of both membrane potential and pH components. A comparison of delta muH+ with delta Gp indicates that the apparent H+/ATP ratio in mung bean mitochondria is 3.4 +/- 0.2 while in phosphorylating sub-mitochondrial particles it is 2.2 +/- 0.1.

Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone↗
PubMed1981

Unusual structures in the epidermal Langerhans' cells of normal human skin.

Two unusual structures were found in the epidermal Langerhans' cells of normal human adult skin: (1) an intramitochondrial crystalline lattice structure composed of numerous electron-dense, fine particles approximately 90 A in diameter, with a lucent spacing of nearly 90 A; (2) bundles of unusual cytoplasmic tubular structures, approximately 120 A wide.

Cytoplasm↗
PubMed1979

Fractionation of human liver mitochondria: enzymic and morphological characterization of the inner and outer membranes as compared to rat liver mitochondria.

The fractionation of human liver mitochondria into inner membrane, outer membrane and matrix material is reported. Compared with rat, human liver mitochondria are more fragile. Fractionation can be achieved in only 2 steps, a digitonin treatment for removal of the outer membrane and centrifugation of the inner membrane plus matrix particles through a linear sucrose gradient resulting in purified inner membranes and matrix.

Animals↗
PubMed1993

Complex I and complex III of mitochondria have common inhibitors acting as ubiquinone antagonists.

Mitochondrial complex I and complex III have common inhibitors with ubiquinone-like structure. The tridecyl analog of stigmatellin, which inhibits mitochondrial complex III at nanomolar concentrations, also inhibits the NADH:ubiquinone reductase activity of complex I at micromolar concentrations. The inhibitor titer depends upon the concentration of the mitochondrial particles and extrapolates to 0.2 microM at zero particle concentration. The stigmatellin analog is more powerful than its parent compound and is noncompetitive with exogenous ubiquinones, rotenone and piericidin. Myxothiazol, which is another potent inhibitor of complex III, is also found to inhibit the activity of complex I with a titer comparable to that of the tridecyl analog of stigmatellin. Additionally, piericidin, which is the most powerful inhibitor of complex I, inhibits the ubiquinol:cytochrome c reductase activity of complex III at micromolar concentrations in mitochondrial particles and at submicromolar concentrations in the isolated enzyme complex.

Animals↗
PubMed1989

Tetraphenylborate potentiates the respiratory inhibition by the dopaminergic neurotoxin MPP+ in both electron transport particles and intact mitochondria.

The cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+) is believed to arise as a consequence of its time- and energy-dependent accumulation inside mitochondria, followed by inhibition of electron transport at Complex I of the respiratory chain. Consistent with our proposal that the accumulation of MPP+ represents a passive Nernstian transport into mitochondria in response to the transmembrane electrochemical potential gradient, tetraphenylborate (TPB-) was found to accelerate the onset of the respiratory inhibition by MPP+ on intact mitochondria. Moreover, the ultimate level of inhibition reached was unexpectedly also increased. The latter is now explained by our finding that TPB- elicits a 12-fold enhancement of MPP+ inhibition of respiration in electron transport particles. It is suggested that TPB- facilitates access of MPP+ to its intramembrane site of inhibitory action in Complex I.

1-Methyl-4-phenylpyridinium↗
PubMed1995

Each domain of the N-ethylmaleimide-sensitive fusion protein contributes to its transport activity.

N-Ethylmaleimide-sensitive fusion protein (NSF) has been shown to be involved in numerous intracellular transport events. In an effort to understand the basic mechanism of NSF in vesicle-target membrane fusion events, we have examined the role that each of its three domains play in how NSF interacts with the SNAP.SNARE complex. Mutagenesis of the first ATP-binding domain (D1, amino acids 206-477) demonstrates that nucleotide binding by this domain is required for 20 S particle assembly. A second mutation, which permits ATP binding but not hydrolysis, yields a protein that can form 20 S particle but fails to mediate its disassembly. Similar mutations of the second ATP-binding domain (D2, amino acids 478-744) result in trimeric molecules that behave like wild type NSF. Domain rearrangement mutants were used to further probe the functional role of each domain. The amino-terminal domain (N, amino acids 1-205) is absolutely required for binding of NSF to the SNAP.SNARE complex, because the truncated mutant, D1D2, is unable to form 20 S particle. When tested as an isolated recombinant protein, the N domain is not sufficient for binding to the SNAP.SNARE complex, but when adjacent to the D1 domain or in a trimeric molecule, the N domain does mediate binding to the SNAP.SNARE complex. Monomeric N-D1 and trimeric N-D2 could both participate in particle formation. Only the N-D1 mutant was able to facilitate MgATP-dependent release from the SNAP.SNARE complex. These data demonstrate that NSF binding to the SNAP.SNARE complex is mediated by the N domain and that both ATP binding and hydrolysis by the D1 domain are essential for 20 S particle dynamics. The intramolecular interactions outlined suggest a mechanism by which NSF may use ATP hydrolysis to facilitate the vesicle fusion process.

Adenosine Triphosphate↗
PubMed1995

The universality of bioenergetic disease and amelioration with redox therapy.

Overt mitochondrial diseases associated with mitochondrial DNA mutations are characterized by a decline in mitochondrial respiratory function. Similarly, a progressive decline in mitochondrial respiratory function associated with mitochondrial DNA mutations is clearly evidenced in aged human subjects. This communication is concerned with the development of a rat model for the study of bioenergy decline associated with the ageing process and overt mitochondrial diseases. The model involves the treatment of young rats with AZT to induce skeletal and cardiac myopathies. It has shown that there is a decline in soleus muscle function in vivo and that this decline is mirrored in the capacity of heart sub-mitochondrial particles to maintain bioenergy function. Coenzyme Q10 and several analogs were administered with AZT as potential therapeutics for the re-energization of affected tissues. Coenzyme Q10 and especially decyl Q were found to be therapeutically beneficial by both in vivo improvement in soleus muscle function and in vitro cardiac mitochondrial membrane potential capacity. Sub-mitochondrial particles were also prepared from heart mitochondria of young and aged rats. The particles prepared from the aged rats were found to have a decreased ability to maintain membrane potential as compared to those derived from the young rats.

Animals↗