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PubMed2000

[Liver steatosis and disorders of mitochondrial oxidative phosphorylation after experimental administration of simazine].

BACKGROUND: Triazine herbicides are widely used in extensive agricultural production, however, some ecological and health hazards occur due to water and food contamination. AIM: The aim of this study was to evaluate the effects of long-term simazine feeding on the steatosis development and the changes of liver bioenergetics in experimental animals. METHODS: A population of B6C3F1 mice were fed with simazine (2 g and 4 g/kg/day, respectively) for 35 weeks. The concentration of cholesterol and triacylglycerols were measured in liver tissue. Liver mitochondria were isolated and parameters of oxidative phosphorylation were assessed polarographically using Clark oxygen electrode with NAD glutamate and/or FAD succinate as substrates. RESULTS: Significant changes (p < 0.001) expressed as medians (with confidence intervals) against control animals were found in both experimental groups after simazine feeding. The concentration of triacylglycerols increased from 10.3 (8.8-10.9) to 20.1 (18.0-20.9) and 47.7 (23.8-56.0), respectively. The parameters of oxidative phosphorylation with NAD substrate glutamate decreased as follows: The index of respiratory control from 7.7 (6.4-9.0) to 4.8 (4.0-6.3) resp. 4.4 (3.9-4.6); the rate of oxygen consumption in the state 3 (with ADP) from 84.2 (82.0-92.3) to 65.4 (50.8-70.7) resp. 69.9 (65.0-78.4) nAtO.mg.prot-1.min-1; and phosporylation rate from 215.3 (204.4-232.2) to 166.3 (120.4-193.6) resp. 169.6 (155.3-176.9) nmolATP.mg.prot-1.min-1. Comparable changes were detected in oxidative phosphorylation with FAD succinate as substrate. CONCLUSIONS: Liver steatosis development and mitochondrial energetics inhibition were determined in mice after long-term simazine feeding, nevertheless, liver energy production was sufficient to satisfy the liver function and the needs of the whole organism. (Tab. 4, Fig. 6, Ref. 24.)

Animals↗
PubMed2001

Mitochondrial medicine--molecular pathology of defective oxidative phosphorylation.

Different tissues display distinct sensitivities to defective mitochondrial oxidative phosphorylation (OXPHOS). Tissues highly dependent on oxygen such as the cardiac muscle, skeletal and smooth muscle, the central and peripheral nervous system, the kidney, and the insulin-producing pancreatic beta-cell are especially susceptible to defective OXPHOS. There is evidence that defective OXPHOS plays an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. Defective OXPHOS may be caused by abnormal mitochondrial biosynthesis due to inherited or acquired mutations in the nuclear (n) or mitochondrial (mt) deoxyribonucleic acid (DNA). For instance, the presence of a mutation of the mtDNA in the pancreatic beta-cell impairs adenosine triphosphate (ATP) generation and insulin synthesis. The nuclear genome controls mitochondrial biosynthesis, but mtDNA has a much higher mutation rate than nDNA because it lacks histones and is exposed to the radical oxygen species (ROS) generated by the electron transport chain, and the mtDNA repair system is limited. Defective OXPHOS may be caused by insufficient fuel supply, by defective electron transport chain enzymes (Complexes I - IV), lack of the electron carrier coenzyme Q10, lack of oxygen due to ischemia or anemia, or excessive membrane leakage, resulting in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase. Human tissues can counteract OXPHOS defects by stimulating mitochondrial biosynthesis; however, above a certain threshold the lack of ATP causes cell death. Many agents affect OXPHOS. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS and induce the 'topical' phase of gastrointestinal ulcer formation. Uncoupled mitochondria reduce cell viability. The Helicobacter pylori induces uncoupling. The uncoupling that opens the membrane pores can activate apoptosis. Cholic acid in experimental atherogenic diets inhibits Complex IV, cocaine inhibits Complex I, the poliovirus inhibits Complex II, ceramide inhibits Complex III, azide, cyanide, chloroform, and methamphetamine inhibit Complex IV. Ethanol abuse and antiviral nucleoside analogue therapy inhibit mtDNA replication. By contrast, melatonin stimulates Complexes I and IV and Gingko biloba stimulates Complexes I and III. Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.

Adenosine Triphosphate↗
PubMed1982

Rate-controlling steps of oxidative phosphorylation in rat liver mitochondria. A synoptic approach of model and experiment.

The contribution of different steps to the control of oxidative phosphorylation in isolated rat liver mitochondria was investigated by a combination of experiments and computer simulations. The parameters of the mathematical model of phosphorylating mitochondria were derived from experimental data. The model correctly described the competition between ATP utilization inside and outside mitochondria for the ATP generated in mitochondria. On the basis of the good agreement between experiments and simulations, the contribution of different steps to the control of respiration was estimated by computing their control strengths, i.e., the influence of their activities on the rate of respiration. The rate-controlling influences vary depending on the load of oxidative phosphorylation. The predominant steps are: in the fully active state (State 3)--the hydrogen supply to the respiratory chain; in the resting state (State 4)--the proton leak of the mitochondrial inner membrane; in states of non-maximum ATP export--the adenine nucleotide translocator. Titrations of respiration with phenylsuccinate, antimycin, oligomycin and carboxyatractyloside completely support these conclusions.

Adenosine Diphosphate↗
PubMed1985

Creatine kinase of rat heart mitochondria. The demonstration of functional coupling to oxidative phosphorylation in an inner membrane-matrix preparation.

To define more clearly the interactions between mitochondrial creatine kinase and the adenine nucleotide translocase, the outer membrane of rat heart mitochondria was removed by digitonin, producing an inner membrane-matrix (mitoplast) preparation. This mitoplast fracton was well-coupled and contained a high specific activity of mitochondrial creatine kinase. Outer membrane permeabilization was documented by the loss of adenylate kinase, a soluble intermembrane enzyme, and by direct antibody inhibition of mitochondrial creatine kinase activity. With this preparation, we documented four important aspects of functional coupling. Kinetic studies showed that oxidative phosphorylation decreased the value of the ternary enzyme-substrate complex dissociation constant for MgATP from 140 to 16 microM. Two approaches were used to document the adenine nucleotide translocase specificity for ADP generated by mitochondrial creatine kinase. Exogenous pyruvate kinase (20 IU/ml) could not readily phosphorylate ADP produced by creatine kinase, since added pyruvate kinase did not markedly inhibit creatine + ATP-stimulated respiration. Additionally, when ADP was produced by mitochondrial creatine kinase, the inhibition of the translocase required 2 nmol of atractyloside/mg of mitoplast protein, while only 1 nmol/mg was necessary when exogenous ADP was added. Finally, the mass action ratio of the mitochondrial creatine kinase reaction exceeded the apparent equilibrium constant when ATP was supplied to the creatine kinase reaction by oxidative phosphorylation. Overall, these results are consistent with much data from intact rat heart mitochondria, and suggest that the outer membrane plays a minor role in the compartmentation of adenine nucleotides. Furthermore, since the removal of the outer membrane does not alter the unique coupling between oxidative phosphorylation and mitochondrial creatine kinase, we suggest that this cooperation is the result of protein-protein proximity at the inner membrane surface.

Animals↗
PubMed1991

Effect of inhibitors of oxidative phosphorylation on erythropoietin mRNA in isolated perfused rat kidneys.

We have used RNase protection to measure oxygen-dependent changes in erythropoietin (EPO) mRNA in isolated perfused kidneys and to compare the effect of hypoxia with the response to inhibitors of oxidative phosphorylation. In well-oxygenated kidneys perfused for 2 h at 12 ml/min, with hematocrit of 0.09 +/- 0.005 and PO2 of 443 +/- 67 mmHg, EPO mRNA levels were similar to the baseline levels measured in nonperfused contralateral kidneys from the same animals. When perfusions were performed under identical conditions but at a PO2 of 32 +/- 4 mmHg, EPO mRNA increased approximately 16-fold. In contrast, graded concentrations of cyanide (10, 100, and 300 microM and 1 mM), antimycin (0.01, 0.1, 0.5, and 1 microM), and oligomycin (0.01, 0.1, and 1 microM) did not alter EPO mRNA in well-oxygenated perfused kidneys. However, in kidneys perfused at low PO2 with a high concentration of each inhibitor, EPO mRNA levels were increased, demonstrating that the ability to respond to hypoxia was retained. Thus inhibitors of oxidative phosphorylation did not mimic the effects of hypoxia, indicating that oxygen-dependent expression of the EPO gene in the kidney is not effected through hypoxic compromise of oxidative phosphorylation.

Animals↗
PubMed2005

An increase in the ATP levels occurs in cerebellar granule cells en route to apoptosis in which ATP derives from both oxidative phosphorylation and anaerobic glycolysis.

Although it is recognized that ATP plays a part in apoptosis, whether and how its level changes en route to apoptosis as well as how ATP is synthesized has not been fully investigated. We have addressed these questions using cultured cerebellar granule cells. In particular, we measured the content of ATP, ADP, AMP, IMP, inosine, adenosine and L-lactate in cells undergoing apoptosis during the commitment phase (0-8 h) in the absence or presence of oligomycin or/and of citrate, which can inhibit totally the mitochondrial oxidative phosphorylation and largely the substrate-level phosphorylation in glycolysis, respectively. In the absence of inhibitors, apoptosis was accompanied by an increase in ATP and a decrease in ADP with 1:1 stoichiometry, with maximum ATP level found at 3 h apoptosis, but with no change in levels of AMP and its breakdown products and with a relatively low level of L-lactate production. Consistently, there was an increase in the cell energy charge and in the ratio ([ATP][AMP])/[ADP](2). When the oxidative phosphorylation was completely blocked by oligomycin, a decrease of the ATP content was found both in control cells and in cells undergoing apoptosis, but nonetheless cells still died by apoptosis, as shown by checking DNA laddering and by death prevention due to actinomycin D. In this case, ATP was provided by anaerobic glycolysis, as suggested by the large increase of L-lactate production. On the other hand, citrate itself caused a small decrease in ATP level together with a huge decrease in L-lactate production, but it had no effect on cell survival. When ATP level was further decreased due to the presence of both oligomycin and citrate, death occurred via necrosis at 8 h, as shown by the lack of DNA laddering and by death prevention found due to the NMDA receptor antagonist MK801. However, at a longer time, when ATP level was further decreased, cells died neither via apoptosis nor via glutamate-dependent necrosis, in a manner similar to something like to energy catastrophe. Our results shows that cellular ATP content increases in cerebellar granule cell apoptosis, that the role of oxidative phosphorylation is facultative, i.e. ATP can also derive from anaerobic glycolysis, and that the type of cell death depends on the ATP availability.

Adenosine Diphosphate↗
PubMedDate not supplied

[Effect of the matrix protein of the influenza virus on oxidative phosphorylation in preparations of isolated liver mitochondria from white mice].

The effect of matrix proteins (M proteins) of influenza A/MRC-11 and B/Lee viruses on oxidative phosphorylation in preparations of isolated mitochondria of white mice liver was studied. M proteins were shown to cause disorders in the system of oxidative phosphorylation leading to reduction of the coefficient of respiratory control and amplification coefficient recorded by the polarographic method. It was also shown that an anti-influenza compound 2-(1'-aminoethyl)-bicyclo(2.2.1)heptane hydrochloride reduced the damaging effect of influenza virus A/MRC-11 M protein but had no influence on the effect on mitochondrial respiration of influenza B/Lee virus M protein.

Animals↗
PubMed2002

Ethanol perfusion increases the yield of oxidative phosphorylation in isolated liver of fed rats.

The question arises as to the effect of ethanol on the actual yield of oxidative phosphorylation in the whole liver because of contradictory results reported in isolated hepatic mitochondria. The adenosine triphosphate (ATP) content of liver isolated from fed rats and perfused in the presence (10 mM) and absence of ethanol was continuously evaluated using 31P Nuclear Magnetic Resonance (NMR). An accurate estimation of mitochondrial ATP synthesis in the whole organ was obtained by subtracting the glycolytic ATP supply from the total ATP production. Simultaneously, the respiratory activity was assessed using O(2) Clark electrodes. The data indicate that ethanol enhanced the net consumption of ATP, leading to a new steady state of the ATP content. ATP synthesis was also found higher under ethanol [1.86+/-0.02 micromol/min g wet weight (min g ww)] than in control [1.44+/-0.18 micromol/min g ww]. However, mitochondrial respiration remained unchanged [2.20+/-0.13 micromol/min g ww] and, consequently, the in situ mitochondrial ATP/O ratio increased from 0.33+/-0.035 (control) to 0.42+/-0.015 (ethanol). The increase of the oxidative phosphorylation yield in the whole liver may be linked to the decrease in cytochrome oxidase activity induced by ethanol [FEBS Lett. 468 (2000) 239]. The significant raise (27%) of the ATP/O ratio was not sufficient to maintain the ATP level following ethanol-increased ATP consumption.

Adenosine Triphosphate↗
PubMed1986

Creatine kinase of heart mitochondria. Control of oxidative phosphorylation by the extramitochondrial concentrations of creatine and phosphocreatine.

Defining how extramitochondrial high-energy phosphate acceptors influence the rates of heart oxidative phosphorylation is essential for understanding the control of myocardial respiration. When the production of phosphocreatine is coupled to electron transport via mitochondrial creatine kinase, the net reaction can be expressed by the balanced equation: creatine + Pi----phosphocreatine + H2O. This suggests that rates of oxygen consumption could be regulated by changes in [creatine], [Pi], or [phosphocreatine], alone or in combination. The effects of altering these metabolites upon mitochondrial rates of respiration were examined in vitro. Rat heart mitochondria were incubated in succinate-containing oxygraph medium (pH 7.2, 37 degrees C) supplemented with five combinations of creatine (1.0-20 mM), phosphocreatine (0-25 mM), and Pi (0.25-5.0 mM). In all cases, the mitochondrial creatine kinase reaction was initiated by additions of 0.5 mM ATP. To emphasize the duality of control, the results are presented as three-dimensional stereoscopic projections. Under physiological conditions, with 5.0 mM creatine, increases in Pi or decreases in phosphocreatine had little influence upon mitochondrial respiration. When phosphocreatine was held constant (15 mM), changes in [creatine] modestly stimulated respiratory rates, whereas Pi again showed little effect. With 1.0 mM Pi, respiration clearly became dependent upon changes in [creatine] and [phosphocreatine]. Initially, respiratory rates increased as a function of [creatine]. However, at [phosphocreatine] values below 10 mM, product "deinhibition" was observed, and respiratory rates rapidly increased to 80% State 3. With 2.0 mM Pi or higher, respiration could be regulated from State 4 to 100% State 3. Overall, the data show how increasing [creatine] and decreasing [phosphocreatine] influence the rates of oxidative phosphorylation when mediated by mitochondrial creatine kinase. Thus, these changes may become secondary cytoplasmic signals regulating heart oxygen consumption.

Animals↗
PubMedDate not supplied

[Effect of nitroglycerin and sodium nitrite on myocardial mitochondrial respiration and oxidative phosphorylation normally and in coronarogenic ischemia].

The effect of nitroglycerin and sodium nitrite (2.10(-6), 2.10(-5) and 2.10(-4) g/ml) on respiration and oxidative phosphorylation of mitochondria of the normal and ischemized dog myocardium has been investigated in the presence of glutamate, succinate and alfaketoglutarate. The drugs inhibited ADP-activated oxygen consumption and ADP phosphorylation rate upon oxidation of succinic acid formed in mitochondria from exogenic glutamate, without changes in the phosphorylation coefficient and free oxidation rate (i. e. in the absence of ADP) in mitochondria of the healthy and ischemic heart. In the ischemic area one can also observe an inhibition of ADP-activated oxidation of endogenic succinate formed from exogenic glutamate.

Animals↗
PubMed1978

Inhibition of bacterial transport by uncouplers of oxidative phosphorylation. Effects of pentachlorophenol and analogues in Bacillus subtilis.

Analogues of the potent uncoupler of oxidative phosphorylation pentachlorophenol were tested as inhibitors of proline and glycine transport by Bacillus subtilis. These analogues included less highly substituted chlorophenols and pentachlorothiophenol. Like pentachlorophenol, they are non-competitive inhibitors of proline transport and uncompetitive inhibitors of glycine transport. However, the less highly substituted chlorophenols are weaker acids than pentachlorophenol and also weaker inhibitors. Analysis indicated that the anionic form of the uncouplers is the inhibiting species. Pentachlorothiophenol, a water-insoluble anion, is also a potent inhibitor. These results support previous studies that concluded that uncouplers of oxidative phosphorylation inhibit amino acid transport by binding at specific sites on proteins, the free energy of interaction stabilizing 'unproductive' conformations. Such specific interactions of uncoupler with protein are probably commonplace.

Bacillus subtilis↗
PubMed2002

Analysis of effects of 2,2',5,5'-tetrachlorobiphenyl on the flux control in oxidative phosphorylation system in rat liver mitochondria.

Modular kinetic analysis reveals that the environmental pollutant 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB) affects a large number of steps in oxidative phosphorylation in rat liver mitochondria. 2,2',5,5'-TCB increases membrane permeability to ions, and inhibits NADH dehydrogenase, cytochrome bc1, cytochrome oxidase (all in the respiratory chain) and ATP-synthase (in the phosphorylation subsystem). Surprisingly, flux control distribution does not change. A kinetic model for oxidative phosphorylation was used to simulate these findings, and it was found that combined large changes in the processes indicated indeed left the flux control largely unchanged. In addition, computational analysis with the model indicated that the adenine nucleotide translocator might be inhibited by 2,2',5,5'-TCB.

Animals↗
PubMed2000

Effects of apolipoproteins C on oxidative phosphorylation in rat liver mitochondria.

It is shown that apoC-III, but not other apoC proteins, components of very low density lipoproteins (apoC-I, apoC-II, apoC-III), reduced the rate of mitochondrial respiration in various metabolic states. This effect depended on the dose of apoprotein, type of oxidized substrate, and the presence of Ca ions in the incubation medium. ApoC-III completely blocked oxidative phosphorylation during oxidation of palmitoyl carnitine by mitochondria, while the respiration rate in metabolic state 4 remained unchanged.

Animals↗
PubMed1956

Oxidative phosphorylation in mitochondria from livers showing cloudy swelling.

Using succinate and alpha-ketoglutarate as substrates, oxidative phosphorylation has been measured in mitochondria isolated from livers showing cloudy swelling. This cellular change was obtained by injecting rats with S. typhi murium toxin and guinea pigs with diphtheria toxin. It has been found that phosphorylation associated with the oxidation of either of these substrates was partially inhibited in mitochondria from livers showing cloudy swelling, while the oxygen consumption was unchanged. Thus, the P:O ratios for both succinate and alpha-ketoglutarate were lower in mitochondria from treated animals than they were in normal mitochondria. Dephosphorylation of ATP was not significantly modified in mitochondria from livers showing cloudy swelling as compared with normal controls. No dephosphorylation of AMP and G-6-P was observed either in normal mitochondria or in mitochondria from treated animals.

Animals↗
PubMed2001

Ethical issues surrounding the evaluation of oxidative phosphorylation disorders in children.

Genetic testing is becoming increasingly frequent as a part of a pediatric evaluation. Oxidative phosphorylation disorders are likewise becoming part of the differential diagnosis for many children with undiagnosed neurologic problems. The complexity of the oxidative phosphorylation pathway and its dual genetic control by nuclear and mitochondrial DNA raise a number of ethical issues dealing mainly with the informed consent process, the respect for a patient's autonomy, the best interest of the patients and their families, as well as issues of genetic discrimination and genetic privacy laws. Open communication with families in pediatric medicine remains the cornerstone of good ethics, along with the skill needed to avoid having ethical issues arise.

Child↗
PubMed1979

[Tissue-specific uncouplers of oxidative phosphorylation in mitochondria from rat heart, kidney, thymus and lung].

The influence of nonmicrosomal cytoplasm fraction from the rat kidney, heart, thymus and lungs on the oxidative phosphorylation of mitochondria (M) of the same tissues and from the ones of the liver and brain was studied. The existence of the tissue-specific uncouplers of the M oxidative phosphorylation was shown in the cross experiments; they were similar to that in the rat liver revealed earlier. A possibility of these regulators participation in the initiation of the M enzymatic degradation process through the activation of phospholipase A when calcium ions leave the M is discussed. The activation under these conditions of the DNA-ase 1, associated with the M membrane, is suggested.

Animals↗
PubMed1990

Oxidative phosphorylation in human muscle in patients with ocular myopathy and after general anaesthesia.

The fuel preference of human muscle mitochondria has been given. Substrates which are oxidized with low velocity cannot be used to detect defects in oxidative phosphorylation. After general anaesthesia, the oxygen uptake with the different substrates is much lower than after local analgesia. The latter was therefore used in the subsequent study. In 15 out of 18 patients with ocular myopathy, defects in oxidative phosphorylation could be detected in isolated muscle mitochondria prepared from freshly biopsied tissue. Measurement of the activity of segments of the respiratory chain in homogenate from frozen muscle showed no, or minor defects. In two of these patients showing exercise intolerance, decreased oxidation of NAD(+)-linked substrates and apparently normal mitochondrial DNA, further study revealed deficiency of pyruvate dehydrogenase in a girl with ptosis and a high Km of complex I for NADH in a man. Both patients responded to vitamin therapy.

Adolescent↗
PubMed2003

[Cyclosporin A inhibits insulin release and down-regulates gene expressions of mitochondrial oxidative phosphorylation enzymes in NIT-cells].

OBJECTIVE: To investigate the effects of cyclosporin A on insulin release and the gene expression profiles of mitochondrial oxidative phosphorylation in NIT-1 cells. METHODS: NIT-1 cells were exposed to cyclosporin A (10 micromol/L) for 24 and 48 h respectively, after which the amount of insulin release was determined by means of radioimmunoassay (RIA), and the differential expressions of Nuox23, Cox7c and Atp5K genes assessed by semi-quantitative reverse transcription polymerase chain reaction. RESULTS: Cyclosporin A reduced insulin release in the cell culture after 24 and 48 h exposure and decreased Nuox23, Cox7c and Atp5K mRNA expressions. CONCLUSION: Cyclosporin A induces inhibition of insulin release in NIT-1 cells, possibly due to the reduction of ATP synthesis involving the down-regulation of the gene expression of mitochondrial oxidative phosphorylation enzymes.

Adenosine Triphosphate↗