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At least 847 records · Page 47Linked to original sources
PubMed2003

Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats.

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes between 3 and 6 mo of age that is associated with insulin resistance. Alterations in hepatic glucose metabolism are known to contribute to the hyperglycemia of diabetes; however, the mechanisms underlying this phenomenon have not been fully explained. To address this issue, intact liver mitochondria were isolated from IUGR and control offspring at different ages to examine the nature and time course of possible defects in oxidative metabolism. Phosphoenolpyruvate carboxykinase (PEPCK) expression was also measured in livers of IUGR and control offspring. Rates of ADP-stimulated (state 3) oxygen consumption were increased for succinate in the fetus and for alpha-ketoglutarate and glutamate at day 1, reflecting possible compensatory metabolic adaptations to acute hypoxia and acidosis in IUGR rats. By day 14, oxidation of glutamate and alpha-ketoglutarate had returned to normal, and by day 28, oxidation rates of pyruvate, glutamate, succinate, and alpha-ketoglutarate were significantly lower than those of controls. Rotenone-sensitive NADH-O2 oxidoreductase activity was similar in control and IUGR mitochondria at all ages, showing that the defect responsible for decreased pyruvate, glutamate, and alpha-ketoglutarate oxidation in IUGR liver precedes the electron transport chain and involves pyruvate and alpha-ketoglutarate dehydrogenases. Increased levels of manganese superoxide dismutase suggest that an antioxidant response has been mounted, and hydroxynonenal (HNE) modification of pyruvate dehydrogenase E2-(catalytic) and E3-binding protein subunits suggests that HNE-induced inactivation of this key enzyme may play a role in the mechanism of injury. The level of PEPCK mRNA was increased 250% in day 28 IUGR liver, indicating altered gene expression of the gluconeogenic enzyme that precedes overt hyperglycemia. These results indicate that uteroplacental insufficiency impairs mitochondrial oxidative phosphorylation in the liver and that this derangement predisposes the IUGR rat to increased hepatic glucose production by suppressing pyruvate oxidation and increasing gluconeogenesis.

Aging↗
PubMed1993

Removal of calcium overload caused by A23187 is more dependent on glycolysis than oxidative phosphorylation.

An increase of cytosol Ca2+ may be the mediator of irreversible cell damage after ATP depletion. Ca2+ influx can also be induced by addition of the ionophore A23187. The extent of cell damage caused by A23187 during concomitant metabolic inhibition was investigated on quiescent fibroblasts. Inhibition of glycolysis resulted in increased cell damage compared to control, whereas an increased rate of glycolysis during inhibition of oxidative phosphorylation attenuated cell damage. These results indicate that glycolysis plays an important part in the removal of entering Ca2+.

Adenosine Triphosphate↗
PubMed1977

[Effect of dextropoxyphene on oxidative phosphorylation in brain and liver of rat (author's transl)].

Dextropropoxyphene hydrochloride increases significantly oxygen uptake in whole rat brain homogenates at concentrations of 10(-4), 10(-5), 10(-6) M when using sucrose 0.25 M pH 7.4 as incubation medium. If substrate and cofactors are added to the sucrose, this drug decreases oxygen uptake at 10(-3) M concentration in brain and liver rat homogenates, and it also decreases significantly the P:O quotient of mitochondria in both organs by uncoupling the oxidative phosphorylation.

Animals↗
PubMedDate not supplied

[Oxidative phosphorylation in different regions of the rat brain following morphine administration].

The influence exercised by morphine in a dose of 20 mg/kg, introduced intraperitoneally, and also in concentrations of 10(-3) and 10(-5) "in vitro" on the parameters of oxidative phosphorylation of the brain cortex and stem of rats was studied. Morphine, used in a concentration of 10(-3), is shown to speed up the substrates oxidation rate. During the first days of its administration the narcotic analgetic inhibited oxidation of mitochondia released from the brain stem, and, once habituation to the narcotic had developed, the inhibition ceased to be effective. In "in vivo" experiments and in vitro tests the effect of phosphorylation remained unchanged. The data obtained suggest that with developing habituation in regard to morphine the functions of the brain stem and cortex mitochondria do not undergo any substantial changes.

Animals↗
PubMedDate not supplied

[Changes in and pharmacological correction of oxidative phosphorylation in regional kidney ischemia].

Respiratory and phosphorylating capacities of kidney mitochondria were distinctly decreased within early (1.5 hr) and late (1 day) postischemic periods after long-term (2-3 hrs) ischemia of rat kidney. Preadministration of adenine (ADP, AMP) and pyridine (NAD) nucleotides into the animals prevented the decreases, while vitamin E, heparin, trifluoroperazine or aminazine proved to be ineffective. Depletion of mitochondrial nucleotide pool, which occurred during long-term ischemia of kidney and were maintained within the post-ischemic period, appears to be responsible for impairment of oxidative phosphorylation.

Animals↗
PubMed2005

Oxidative phosphorylation and the tricarboxylic acid cycle are essential for normal development of mouse ovarian follicles.

BACKGROUND: Mouse ovarian follicles are typically grown in upright drops of culture medium. Recently we found that culture of follicles at the medium-gas interface in inverted drops markedly improved follicular development, possibly due to improved access of oxygen to the follicle. In this study, we examined the importance of aerobic energy metabolism for follicle development by culturing mouse follicles (198 6 16.5 initial microm diameter, mean 6 SD) in the presence of phosphorylation and tricarboxylic acid (TCA) cycle inhibitors. METHODS: All inhibitors were tested in the inverted system using 100 microl medium drops in 96-well plates; certain inhibitors were also tested in upright drops with or without an oil overlay. RESULTS: The oxidative phosphorylation inhibitor rotenone (0.1, 0.5 and 1 micromol/l) totally abolished follicle growth in the inverted system; cyanide (1 mmol/l) totally abolished growth in the upright with oil system but not in the inverted system (possibly due to loss of cyanide gas due to the absence of an oil overlay). The mitochondrial uncoupler 2,4-dinitrophenol (0.5 and 1 mmol/l) also abolished growth in the inverted system. The TCA cycle inhibitor monofluoroacetate (10 mmol/l), significantly inhibited growth in all three culture systems (P < 0.01) but malonate (10 mmol/l) had no effect. CONCLUSIONS: Aerobic metabolism and an adequate oxygen supply are essential for normal follicular development.

2,4-Dinitrophenol↗
PubMed1990

Studies on the mechanism of oxidative phosphorylation. Positive cooperativity in ATP synthesis.

Kinetic and nucleotide binding studies have shown that submitochondrial particles from bovine heart possess three exchangeable binding sites for ADP or GDP. In order of decreasing affinity at neutral pH, these sites will be referred to as sites I, II, and III, and their respective dissociation constants as KI, KII, and KIII. In oxidative phosphorylation experiments in the presence of saturating amounts of inorganic phosphate, rapid ATP (or GTP) synthesis occurred only upon ADP (or GDP) binding to site III. The Eadie-Hofstee plots (v/[S] on the ordinate versus v on the abscissa) of the kinetics of ATP (or GTP) synthesis at variable ADP (or GDP) were, therefore, composed of an initial upward phase, indicating positive cooperativity with respect to substrate concentration, followed by a downward phase where rapid product formation took place. These data allowed calculation of KII from the upward phase and KIII (equivalent to apparent Km) from the downward phase. KI was estimated from Scatchard plots of binding data with radiolabeled ADP or GDP. Thus, together with our previous results, these findings have allowed characterization of the process of ATP or GTP synthesis by bovine-heart submitochondrial particles in terms of KI, KII, KIII, and kcat.

Adenosine Diphosphate↗
PubMed1975

[Respiration and oxidative phosphorylation in isolated liver cells].

Two methods of preparation of isolated rat liver cells were studied. In the first method, the dissociative effect of enzymes and mechanical treatment and Hanks' solution as isolation medium were used. In the second method, enzymes were replaced by compexon-ethylenediamine tetraacetate and Hanks' solution -- by 0.25 M sucrose. The cells obtained by the second method are able of oxidative phosphorylation and keep better NAD-H-cytochrom c-reductase. The fine structure of these cells revealed by means of electron microscopy analysis was well preserved.

Animals↗
PubMed1971

Oxidative phosphorylation in Escherichia coli K12. Mutations affecting magnesium ion- or calcium ion-stimulated adenosine triphosphatase.

1. Two mutants of Escherichia coli K 12 were isolated which, although able to grow on glucose, are unable to grow with succinate or d-lactate as the sole source of carbon. 2. Genetic mapping of these mutants showed that they both contain a mutation in a gene (designated uncA) mapping at about minute 73.5 on the E. coli chromosome. 3. The uncA(-) alleles were transferred by bacteriophage-mediated transduction into another strain of E. coli and the transductants compared with the parent strain to determine the nature of the biochemical lesion in the mutants. 4. The mutants gave low aerobic growth yields when grown on limiting concentrations of glucose, but oxidase activities in membranes from both the mutants and the normal strain were similar. 5. Measurement of P/O ratios with d-lactate as substrate indicated that a mutation in the uncA gene causes uncoupling of phosphorylation associated with electron transport. 6. Determination of the Mg(2+),Ca(2+)-stimulated adenosine triphosphatase activities in the mutant and normal strains indicated that the uncA gene is probably the structural gene for Mg(2+),Ca(2+)-stimulated adenosine triphosphatase. 7. Mg(2+),Ca(2+)-stimulated adenosine triphosphatase therefore appears to be essential for oxidative phosphorylation in E. coli.

Adenosine Triphosphatases↗
PubMed1984

Effects of ticlopidine, a new platelet antiaggregating agent, and its analogues on mitochondrial metabolism. Oxidative phosphorylation, protein synthesis and DNA polymerase activity.

The effects of ticlopidine and six of its analogues on mitochondrial functions were studied in isolated rat liver mitochondria. The influence of ticlopidine and each of the following analogues: PCR 5325, PCR 4099, PCR 3787, PCR 2362, PCR 4499 and PCR 0665 was evaluated by determining their interaction with three major mitochondrial activities. (A) Oxidative phosphorylation, measured by oxypolarography, was assayed in the presence of glutamate or succinate as source of energy, and both State 4 and State 3 were recorded. Ticlopidine, at 20 micrograms/ml, slightly increased glutamate State 4, whereas it was without effect on that of succinate. At higher concentration (40 micrograms/ml), ticlopidine caused 40-45% inhibition of State 4 with both substrates. All the other analogues tested at either 20 or 40 micrograms/ml were virtually without effect on the respiration. However, at 20 micrograms/ml, ticlopidine and some of its analogues inhibited mitochondrial State 3, while under similar conditions other analogues had little or no effect on this state. (B) Mitochondrial protein synthesis, measured by [14C]-L-leucine incorporation, was not affected significantly by any of these drugs. Whereas chloramphenicol at 10 micrograms/ml caused 80% inhibition, ticlopidine and its analogues in concentrations inhibitory to State 3 did not inhibit mitochondrial protein synthesis. (C) Mitochondrial DNA polymerase activity, determined by [3H] thymidine 5'-triphosphate incorporation, was not inhibited by these drugs. We conclude that, while ticlopidine and analogues have little or no effect on either mitochondrial protein synthesis or mitochondrial DNA polymerase activity, ticlopidine and some of its analogues are inhibitory of the energy conserving mechanism in mitochondria.

Animals↗
PubMed1989

[The role of long-chain acyl-CoA in the disturbances of oxidative phosphorylation in the myocardium].

The effect of intramitochondrial acyl-CoA on the respiration of rabbit heart mitochondria in different metabolic states was studied. Acyl-CoA inhibited O2 consumption by 11% in State 4 and by 6% in State 3. However, the effect of acyl-CoA was more pronounced (20%) in the intermediate state of respiration between State 4 and State 3. The data obtained suggest that acyl-CoA can regulate oxidative phosphorylation in heart mitochondria in vivo.

Acyl Coenzyme A↗
PubMed2003

Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease.

In vivo, post-mortem and biopsy data suggest that coupled declines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.

Alzheimer Disease↗
PubMed1979

[Effect of aflatoxin B 1 on respiration and oxidative phosphorylation in the rabbit. II. Research on cardiac and renal mitochondria].

The effect of various concentrations of aflatoxin B1 (AB1) is studied "in vitro" on heart (HM) and kidney mitochondria of rabbit (KM). AB1 inhibits (4 x 10(-4)M) the respiratory rate up to a maximum 50-35% in HM and 28-35% in KM by glutamate and succinate as substrates respectively, but it does not uncouple oxidative phosphorylation nor does it inhibit site III (ascorbate + TMPD). The inhibited site appears to be between cytochromes b and c (c1). AB1 seems to be easily transported across heart mitochondrial membrane. The relevance of these findings to liver cell necrosis promoted by aflatoxin is discussed.

Aflatoxins↗
PubMed1979

Oxidative phosphorylation in pea cotyledon submitochondrial particles.

Mitochondria and submitochondrial particles (SMP) from pea cotyledons were shown to catalyze oxidative phosphorylation as measured by (32)Pi uptake into phosphate esters. ATP synthesis was sensitive to the electron transport inhibitor KCN, the uncoupler carbonyl cyanide m-chlorophenylhydrazone, and the coupling factor inhibitor oligomycin. Experiments with the adenine nucleotide translocator inhibitor atractyloside indicated the SMP were inside-out. Mersalyl completely inhibited ATP synthesis by SMP, and a separate experiment indicated that mersalyl has a direct effect on the ATPase complex. The kinetics of ATP synthesis indicated a high affinity for phosphate (K(m) = 0.18 millimolar). ADP kinetics gave a biphasic curve with K(m) values of about 4.8 and 160 micromolar. O(2) uptake and ATP synthesis had a pH maximum of 7.6 while the ratio of micromoles phosphate esterified to microatoms O(2) taken up was highest at pH 7.2. Sodium chloride inhibited both ATP synthesis and O(2) uptake but stimulated the ATPase reaction. The SMP also catalyzed a slow ATP-phosphate exchange reaction.

Journal Article↗
PubMed1996

Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease.

In vivo imaging of patients with Alzheimer's disease using positron emission tomography (PET) demonstrates progressive reductions in brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. These reductions likely follow regional synaptic loss or dysfunction and reflect physiological down-regulation of gene expression for glucose delivery, oxidative phosphorylation (OXPHOS), and energy consumption in brain. Indeed, the pattern of down-regulation of expression for both mitochondrial and nuclear genes coding for subunits of OXPHOS enzymes in the Alzheimer brain resembles the pattern of down-regulation in normal brain caused by chronic sensory deprivation. In both cases, down-regulation likely is mediated by changes in transcriptional and posttranscriptional regulatory factors. Physiological down-regulation of OXPHOS gene expression in Alzheimer's is consistent with PET evidence that cognitive or psychophysical activation of mildly to moderately demented Alzheimer's patients can augment brain-blood flow and glucose metabolism to the same extent as in control subjects. If the primary neuronal defect that leads to reduced brain energy demand in Alzheimer's disease could be prevented or treated, brain glucose transport and OXPHOS enzyme activities might recover to normal levels.

Alzheimer Disease↗