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PubMed1981

Effects of growth hormone on the oxidation of [1-14C]-pyruvate in adipose tissue of hypophysectomized rats.

The acute effects of growth hormone on the oxidation of [1-14C]-pyruvate to 14CO2 were studied in epididymal adipose tissue obtained from hypophysectomized rats. At concentrations ranging from 10 ng/ml to 1 microgram/ml, growth hormone increased the rate of pyruvate oxidation by 20-60%. A lag period of up to 30 min was required for the full effect of the hormone to develop. Addition of fructose to the incubation medium increased the rate of pyruvate oxidation in response to either growth hormone or insulin. The effects of 1 microgram/ml growth hormone were comparable in magnitude to those of 1 mU/ml insulin, and pyruvate oxidation in the presence of both agents was no greater than in the presence of either on its own. The enhancement of pyruvate oxidation by growth hormone, like that caused by insulin, probably results from activation of pyruvate dehydrogenase. Increased activity of pyruvate dehydrogenase was found in cell-free extracts of adipose tissue that had been exposed to either growth hormone or insulin. The response of tissue segments to growth hormone followed the same pattern as observed for other acute insulin-like effects of the hormones; it was transient and disappeared within 3 hours despite continued presence of the hormone. Previous exposure of the tissues to growth hormone made them refractory to the hormone upon reexposure.

Adipose Tissue↗
PubMed2004

Quantitative NAD(P)H/flavoprotein autofluorescence imaging reveals metabolic mechanisms of pancreatic islet pyruvate response.

Glucose-stimulated insulin secretion is a multistep process dependent on beta-cell metabolic flux. Our previous studies on intact pancreatic islets used two-photon NAD(P)H imaging as a quantitative measure of the combined redox signal from NADH and NADPH (referred to as NAD(P)H). These studies showed that pyruvate, a non-secretagogue, enters beta-cells and causes a transient rise in NAD(P)H. To further characterize the metabolic fate of pyruvate, we have now developed one-photon flavoprotein microscopy as a simultaneous assay of lipoamide dehydrogenase (LipDH) autofluorescence. This flavoprotein is in direct equilibrium with mitochondrial NADH. Hence, a comparison of LipDH and NAD(P)H autofluorescence provides a method to distinguish the production of NADH, NADPH, or both. Using this method, the glucose dose response is consistent with an increase in both NADH and NADPH. In contrast, the transient rise in NAD(P)H observed with pyruvate stimulation is not accompanied by a significant change in LipDH, which indicates that pyruvate raises cellular NADPH without raising NADH. In comparison, methyl pyruvate stimulated a robust NADH and NADPH response. These data provide new evidence that exogenous pyruvate does not induce a significant rise in mitochondrial NADH. This inability likely results in its failure to produce the ATP necessary for stimulated secretion of insulin. Overall, these data are consistent with either a restricted pyruvate dehydrogenase-dependent metabolism or a buffering of the NADH response by other metabolic mechanisms.

Animals↗
PubMed1982

Control of pyruvate kinase activity during glycolysis and gluconeogenesis in Propionibacterium shermanii.

The concentrations of glycolytic intermediates and ATP and the activities of certain glycolytic and gluconeogenic enzymes were determined in Propionibacterium shermanii cultures grown on a fully defined medium with glucose, glycerol or lactate as energy source. On all three energy sources, enzyme activities were similar and pyruvate kinase was considerably more active than the gluconeogenic enzyme pyruvate, orthophosphate dikinase, indicating the need for regulation of pyruvate kinase activity. The intracellular concentration of glucose 6-phosphate, a specific activator of pyruvate kinase in this organism, changed markedly according to both the nature and the concentration of the growth substrate: the concentration (7-10 mM) during growth with excess glucose or glycerol was higher than that (1-2 mM) during growth with lactate or at growth-limiting concentrations of glycerol or glucose. Other glycolytic intermediates, apart from pyruvate, were present at concentrations below 2 mM. Glucose 6-phosphate overcame inhibition of pyruvate kinase activity by ATP and inorganic phosphate. With 1 mM-ATP and more than 10 mM inorganic phosphate, a change in glucose 6-phosphate concentration from 1-2 mM was sufficient to switch pyruvate kinase from a strongly inhibited to a fully active state. The results provide a plausible mechanism for the regulation of glycolysis and gluconeogenesis in P. shermanii.

Adenosine Triphosphate↗
PubMed1985

Specific replacements of pyruvate for trophic support of central and peripheral nervous system neurons.

When embryonic central nervous system neurons are seeded at low densities with Eagle's basal medium supplemented with the serum substitute N1, glucose, and glutamine, neuronal survival for even 24 h requires the additional supply of exogenous pyruvate--and so does the survival of many peripheral nervous system neurons. Pyruvate can be replaced by alpha-ketoglutarate or oxaloacetate, but not by Krebs cycle substrates that are not keto acids. Most other alpha-keto acids tested (though not beta- or gamma-keto acids) also mimic pyruvate. The apparent equivalence to pyruvate of all these compounds includes identical ED50 values (300 microM for embryonic avian fore-brain neurons, 30-40 microM for rat hippocampal neurons), and also identical susceptibilities to the pyruvate-sparing effects of other low-molecular-weight agents present in Dulbecco's modified Eagle's medium or in astroglia conditioned medium. The substitute alpha-keto acids, however--unlike pyruvate, alpha-ketoglutarate, or oxaloacetate--support cell survival only in the presence of alpha-amino acids that transaminate to alpha-ketoglutarate, oxaloacetate, or pyruvate. The alpha-keto acids, therefore, operate as acceptors of amino groups from appropriate donors to generate Krebs cycle-relevant substrates. Consistent with this view, [14C]glutamate did not generate appreciable 14CO2 unless accompanied by a suitable alpha-keto acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1974

Pyruvate carboxylase deficiency in pleiotropic carbohydrate-negative mutant strains of Pseudomonas aeruginosa.

Cell extracts of Pseudomonas aeruginosa strain PAO were found to contain pyruvate carboxylase activity. Specific activities were minimal when cells were grown on Casamino Acids, acetate, or succinate, but were three- to fourfold higher when cells were grown in glucose, gluconate, glycerol, lactate, or pyruvate minimal media. The reaction in crude cell extracts and in partially purified preparations was dependent on pyruvate, adenosine 5'-triphosphate, and Mg(2+), but was not affected by either the presence or absence of acetyl coenzyme A. Activity was nearly totally inhibited by avidin and this inhibition was substantially blocked by free biotin in incubation mixtures. Cell extracts were shown to fix (14)CO(2) in a reaction that had these same characteristics. Eight pleiotropic, carbohydrate-negative mutant strains of the organism were isolated after nitrosoguanidine mutagenesis. Each mutant strain grew normally in acetate, succinate, and citrate minimal media but failed to utilize glucose, gluconate, 2-ketogluconate, mannitol, glycerol, lactate, and pyruvate as sole sources of carbon and energy. These strains were found by quantitative transductional analysis with phage F116 to form a single linkage group. Cell extracts of each mutant strain were either lacking or severely deficient in pyruvate carboxylase activity. Spontaneous revertants of five of the eight strains were isolated and found to recover simultaneously both pyruvate carboxylase activity and the ability to utilize each of the C(6) and C(3) compounds. A second linkage group of similar mutant strains that grew on the C(3) compounds was found to contain normal levels of pyruvate carboxylase activity, but each strain was deficient in an enzyme of the Entner-Doudoroff pathway.

Adenosine Triphosphate↗
PubMed2001

Acute hibernation decreases myocardial pyruvate carboxylation and citrate release.

In the well-perfused heart, pyruvate carboxylation accounts for 3-6% of the citric acid cycle (CAC) flux, and CAC carbon is lost via citrate release. We investigated the effects of an acute reduction in coronary flow on these processes and on the tissue content of CAC intermediates. Measurements were made in an open-chest anesthetized swine model. Left anterior descending coronary artery blood flow was controlled by a extracorporeal perfusion circuit, and flow was decreased by 40% for 80 min to induce myocardial hibernation (n = 8). An intracoronary infusion of [U-(13)C(3)]lactate and [U-(13)C(3)]pyruvate was given to measure the entry of pyruvate into the CAC through pyruvate carboxylation from the (13)C-labeled isotopomers of CAC intermediates. Compared with normal coronary flow, myocardial hibernation resulted in parallel decreases of 65% and 79% in pyruvate carboxylation and net citrate release by the myocardium, respectively, and maintenance of the CAC intermediate content. Elevation of the arterial pyruvate concentration by 1 mM had no effect. Thus a 40% decrease in coronary blood flow resulted in a concomitant decrease in pyruvate carboxylation and citrate release as well as maintenance of the CAC intermediates.

Acute Disease↗
PubMed1994

Effect of hepatic portal infusion of pyruvate on pancreatic hormone response during exercise.

The purpose of the present investigation was to evaluate the effects of a small infusion of pyruvate into the hepatic portal vein on the pancreatic hormone response during exercise (30-min treadmill run; 26 m/min, 0% grade) in adrenodemedullated rats. Resting and exercising rats were infused with either pyruvate (5% solution; 0.016 ml/min) into the portal vein, pyruvate into the jugular vein, or saline into the portal vein. Peripheral and portal blood glucose concentrations were decreased (P < 0.01) similarly in all groups after the exercise period. Peripheral insulin, glucagon, and norepinephrine levels, either at rest or after exercise, were not significantly affected by the infusions. The response of portal pancreatic hormone concentrations to exercise was, however, reduced by the pyruvate infused into the portal and jugular veins for insulin and into the portal vein only for glucagon. The normal increase in peripheral glucagon-insulin molar ratio during exercise was shut down by the infusion of pyruvate into the portal vein but not by the infusion of pyruvate into the jugular vein or by the infusion of saline. These results indicate that a small blood infusion of pyruvate, even in the presence of a decreasing blood glucose level, can attenuate substantially the pancreatic hormone response during exercise in adrenodemedullated rats.

Animals↗
PubMed1976

Fatal lactic acidosis in a newborn attributable to a congenital defect of pyruvate dehydrogenase.

An infant suffering from metabolic acidosis attributable to hyperlactatemai (6.1 mmol/liter) accompanied by hyperalaninemia (1 mmol/liter) and hyperserinemia (0.6 mmol/liter) is described. The urinary excretion of lactate and pyruvate was greatly elevated; the lactate to pyruvate ratio was normal. The urine showed low levels of citrate, isocitrate, and cis-aconitate, and low or normal levels of alpha-oxoglutarate, succinate, malate, and methylmalonate. Aspartate was slightly elevated in serum and urine, indicating a corresponding increase if its alpha-ketoacid oxaloacetatae. These patterns of organic acids and amino acids suggested an in vivo defect in the oxidation of pyruvate. Fibroblasts cultured from skin biopsy from the patient metabolized radioactive pyruvate (final concentration 0.04-2 mmol/liter) to CO2 at rates from 5 to 17% of that of fibroblasts from normal control subjects. Enzyme studies with fibroblast sonicates revealed a severe deficiency of the pyruvate dehydrogenase complex (about 8% of normal), and this error was localized to the first unit of the complex, i.e., the pyruvate dehydrogenase (about 4% of normal). Fibroblasts from both parents metabolized pyruvate to CO2 at a slightly reduced rate, suggesting parental heterozygosity.

Acidosis↗
PubMed1976

A possible mechanism for selective cerebellar damage in partial pyruvate dehydrogenase deficiency.

In patients with partial deficiencies of pyruvate dehydrogenase, cerebellar ataxia has been the most prominent and sometimes the only neurologic abnormality. It is not clear how this generalized enzyme deficiency (with activity 15 to 30 percent of normal in several tissues) might lead to clinical signs referable to a limited part of the nervous system. We therefore compared the normal activity of pyruvate dehydrogenase with the normal rate of pyruvate oxidation in different parts of animal brains and then calculated the effect on pyruvate oxidation of partial deficiencies of the enzyme. The data indicate that pyruvate oxidation could be impaired in an area of anterior cerebellar vermis by deficiencies of pyruvate dehydrogenase too mild to affect pyruvate oxidation in the other areas of the brain we examined.

Animals↗
PubMed1993

Effects of pyruvate and glucose on the development of human preimplantation embryos in vitro.

Although human embryos will develop in vitro for six days or more, little is known about the effects of the primary nutrients, pyruvate and glucose, on development. Because the nutrient requirements of embryos change throughout preimplantation development, the effects of altering substrate concentrations in the culture medium were examined, using 'surplus' human preimplantation embryos cultured from the two-four-cell stage to the blastocyst stage in medium containing various concentrations of pyruvate and glucose. Between the one-cell stage and the two-four-cell stage all of the embryos were exposed to 0.47 mmol pyruvate l-1 and 5.5 mmol glucose l-1. Pyruvate as sole substrate in the medium could support blastocyst development to an extent of 59% (10 of 17). Conversely, culture of embryos in pyruvate-free medium resulted in the developmental arrest of 84% (21 of 25) of embryos, and for the 16% (4 of 25) that did reach the blastocyst stage there was a significant decrease in metabolic activity on day 4-5, during the morula to blastocyst stage transition. Embryos could not use glucose to compensate for the lack of pyruvate in the medium. Pyruvate uptake was related to exogenous concentration and optimal development occurred at the highest concentration tested, 0.47 mmol l-1. Embryo development to the eight-cell stage was slightly enhanced 82% (14 of 17) versus 60% (24 of 40) when no glucose was added to the medium, and the resulting blastocysts had significantly more cells (99.1 +/- 13.5 versus 58.4 +/- 8.2; P < 0.02) than did embryos grown in the presence of 1 mmol glucose l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Blastocyst↗
PubMed1976

[Cooperative interaction of pyruvate dehydrogenase from pigeon breast muscle].

Cooperative interaction of pyruvate with the pyruvate dehydrogenase (PD) complex from pigeon breast muscle was shown. The sigmoidal dependence of the reaction rate on pyruvate concentration was observed for the PD complex. The Hill coefficient is equal to 1,5; no inhibition by the substrate (up to 2.2.10(-3) M) was found. The kinetic behaviour of the isolated pyruvate dehydrogenase component (PDH) analyzed under similar conditions, is more complex; this may be probably due to the presence of oligomeric forms with different molecular weights and specific activities. The competitive inhibitor of the PD complex--an amide of pyruvic acid (PA) (Ki=6.3-10(-6) M) activates the enzyme at low concentrations (less than 2,10(-6) M). When PA is present, the dependence of the reaction rate on pyruvate concentration gives a usual hyperbolic curve, v of [S]o. It is concluded that pyruvate may have a regulatory effect on the activity of muscle PD complex.

Animals↗
PubMed2000

Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression.

Using immunoblot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoenzymes PDK2 and PDK4, we demonstrate selective changes in PDK isoenzyme expression in slow-twitch versus fast-twitch skeletal muscle types in response to prolonged (48 h) starvation and refeeding after starvation. Starvation increased PDK activity in both slow-twitch (soleus) and fast-twitch (anterior tibialis) skeletal muscle and was associated with loss of sensitivity of PDK to inhibition by pyruvate, with a greater effect in anterior tibialis. Starvation significantly increased PDK4 protein expression in both soleus and anterior tibialis, with a greater response in anterior tibialis. Starvation did not effect PDK2 protein expression in soleus, but modestly increased PDK2 expression in anterior tibialis. Refeeding for 4 h partially reversed the effect of 48-h starvation on PDK activity and PDK4 expression in both soleus and anterior tibialis, but the response was more marked in soleus than in anterior tibialis. Pyruvate sensitivity of PDK activity was also partially restored by refeeding, again with the greater response in soleus. It is concluded that targeted regulation of PDK4 isoenzyme expression in skeletal muscle in response to starvation and refeeding underlies the modulation of the regulatory characteristics of PDK in vivo. We propose that switching from a pyruvate-sensitive to a pyruvate-insensitive PDK isoenzyme in starvation (a) maintains a sufficiently high pyruvate concentration to ensure that the glucose-->alanine-->glucose cycle is not impaired, and (b) may 'spare' pyruvate for anaplerotic entry into the tricarboxylic acid cycle to support the entry of acetyl-CoA derived from fatty acid (FA) oxidation into the tricarboxylic acid cycle. We further speculate that FA oxidation by skeletal muscle is both forced and facilitated by upregulation of PDK4, which is perceived as an essential component of the operation of the glucose-FA cycle in starvation.

Animals↗
PubMed2000

Conversion of Escherichia coli pyruvate oxidase to an 'alpha-ketobutyrate oxidase'.

Escherichia coli pyruvate oxidase (PoxB), a lipid-activated homotetrameric enzyme, is active on both pyruvate and 2-oxobutanoate ('alpha-ketobutyrate'), although pyruvate is the favoured substrate. By localized random mutagenesis of residues chosen on the basis of a modelled active site, we obtained several PoxB enzymes that had a markedly decreased activity with the natural substrate, pyruvate, but retained full activity with 2-oxobutanoate. In each of these mutant proteins Val-380 had been replaced with a smaller residue, namely alanine, glycine or serine. One of these, PoxB V380A/L253F, was shown to lack detectable pyruvate oxidase activity in vivo; this protein was purified, studied and found to have a 6-fold increase in K(m) for pyruvate and a 10-fold lower V(max) with this substrate. In contrast, the mutant had essentially normal kinetic constants with 2-oxobutanoate. The altered substrate specificity was reflected in a decreased rate of pyruvate binding to the latent conformer of the mutant protein owing to the V380A mutation. The L253F mutation alone had no effect on PoxB activity, although it increased the activity of proteins carrying substitutions at residue 380, as it did that of the wild-type protein. The properties of the V380A/L253F protein provide new insights into the mode of substrate binding and the unusual activation properties of this enzyme.

Amino Acid Substitution↗
PubMed1975

Regulation of pyruvate dehydrogenase in isolated rat liver mitochondria. Effects of octanoate, oxidation-reduction state, and adenosine triphosphate to adenosine diphosphate ratio.

Factors which influence the distribution of pyruvate dehydrogenase between its active, unphosphorylated form (PDHa) and its inactive, phosphorylated form (PDHb) have been examined in isolated rat liver mitochondria. A rapid freezing method was developed for the extraction of pyruvate dehydrogenase from incubated mitochondria which prevented interconversions between PHDa and PDHb which normally occur when mitochondria are collected by centrifugal methods. The intramitochondrial ATP:ADP ration was varied over a 100-fold range by the addition of dinitrophenol, oligomycin, or both substances to mitochondria oxidizing 2-oxoglutarate. PDHa activity was found to be inversely proportional to the intramitochondrial ATP:ADP ratio but was not closely correlated with the extramitochondrial adenine nucleotide levels. When mitochondria were incubated in State 4 with succinate and rotenone, the addition of pyruvate increased PDHa activity more than 10-fold without appreciably altering the mitochondrial ATP:ADP ratio. These observations are most readily explained by the known inhibitory effects of pyruvate and ADP on PDHa kinase. PDHa activity could be maintained at a high level by incubating mitochondria in a condition resembling State 3 by the addition of succinate, glucose, and hexokinase. The further addition of octanoate reduced PDHa activity by 60% without appreciably altering the ATP:ADP ratio. Rotenone had a sililar effect. When added in the presence of octanoate, rotenone further decreased PDHa activity whereas 4-pentenoate led to an increase in activity. The effects of octanoate on PDHa activity were not seen when mitochondria were incubated in the presence of high levels of pyruvate, though pyruvate oxidation was till diminished by over 50%. The data suggest that octanoate addition favors the PDHa kinase reaction leading to inactivation of PDHa, and in addition causes the accumulation of NADH and acetyl-CoA which are recognized competitive inhibitors of pyruvate dehydrogenase.

Adenosine Diphosphate↗
PubMed1992

Gluma shear bond strength to enamel and dentin treated with pyruvic acid and glycine.

The purpose of this study was to determine the effect of pyruvic acid and glycine on the shear bond strength (SBS) of the Gluma Bonding System to dentin and enamel. Forty-five mandibular and maxillary permanent first and second molars and 45 maxillary permanent central incisors were used in the study. Fifteen test specimens were prepared with each of the following procedures. Dentin: using the conventional Gluma Bonding System (A); the Gluma 2 Cleanser was replaced with 10% pyruvic acid containing 10% glycine with pH 2.8 (B); or the dentin was etched with 10% pyruvic acid (pH 1.5) followed by the application of 10% glycine with pH adjusted to 9.0 (C). Enamel: etched with Gluma 1 Etchant (D); etched with 10% pyruvic acid containing 10% glycine (E); or etched with 10% pyruvic acid followed by the application of 10% glycine (F). The test specimens were disassembled 15 minutes after cure, stored in physiological saline at 37 degrees C for 24 hours, and the SBS determined in an Instron machine at a crosshead speed of 0.5 mm.min.-1 The SBS was expressed in MPa. The data were analyzed by ANOVA and the Student-Newman-Keuls test. The mean +/- SD of the SBS in MPa were: A: 8.7 +/- 5.2; B: 14.7 +/- 4.6; C: 12.8 +/- 4.8; D: 19.8 +/- 3.8; E: 18.0 +/- 3.1; F: 17.6 +/- 3.5. The application of 10% pyruvic acid containing 10% glycine, and 10% pyruvic acid followed by 10% glycine, resulted in a significant increase in SBS to dentin. The SBS to enamel treated with the three procedures were not significantly different.

Acid Etching, Dental↗
PubMed1990

[Changes in ketone body ratio and levels of pyruvate and lactate in arterial blood of patients with hepatocellular carcinoma after transcatheter arterial embolization].

The ketone body ratio (acetoacetate/3-hydroxybutyrate:KBR) and levels of pyruvate and lactate in arterial blood of patients with hepatocellular carcinoma (HCC) were examined. KBRs and levels of pyruvate and lactate in patients with HCC were similar to those in patients without liver diseases (1.57 +/- 0.88, 0.84 +/- 0.32, 11.4 +/- 4.5 vs 1.80 +/- 0.9, 0.89 +/- 0.48, 10.8 +/- 6.2). However, pyruvate to lactate ratios were significantly lower in HCC patients (7.45 +/- 1.57 vs 8.62 +/- 2.15, p less than 0.05). Among the HCC patients the levels of pyruvate and lactate were significantly higher in patients with liver cirrhosis (LC) than those in patients without LC. The sequential changes of KBRs and levels of pyruvate and lactate were examined before and after transcatheter arterial embolization (TAE). Although KBRs were transiently decreased immediately after TAE, they were at higher levels from the 3rd to 21st day in comparison with those before TAE. The levels of pyruvate and lactate showed no significant changes immediately after TAE. However, they followed a course similar to that of KBRs after TAE. Lower KBRs and higher levels of pyruvate and lactate tended to be observed in HCC patients with LC after TAE than in those without LC. This suggests a decrease of intrahepatic blood flow probably due to histological reconstruction. These results suggest that the presence of LC is one of the most important factors influencing the functional reserve of liver in HCC patients. In HCC patients without LC, the recovery from the overload of TAE may operate at mitochondrial levels at least the 3rd day after TAE.

Carcinoma, Hepatocellular↗
PubMed1989

[Effect of acute poisoning of rats with carbaryl on transamination reactions with involving pyruvate. III. Supplementary studies of plasma aminotransferases].

Male Wistar rats were poisoned orally with one carbaryl dose 474 mg/kg (1/2 DL50). After 2, 4, 24 and 72 hours from the administration of the insecticide the activity of plasma aminotransferases catalysing the reactions between pyruvate and the following amino acids: asparagine, aspartic acid, glutamic acid, isoleucine, lysine and valine was determined. Under physiological conditions these amino acids are not participating in the transamination reactions. The activity of aminotransferases was expressed as the amount of alanine developing during incubation of 1 ml of plasma for 1 hour. Alanine was determined spectrophotometrically after chromatographic separation on paper. The results of the investigations demonstrated that acute poisoning with carbaryl caused the appearance of activity of all studied plasma aminotransferases, except for the enzyme catalysing the reaction between pyruvate and lysine. The activity of the studied aminotransferases appeared as follows: glutamic acid--pyruvate--4 hr; isoleucine--pyruvate--24 and 72 hr; asparagine--pyruvate, aspartic acid--pyruvate and valine--pyruvate--72 hr after intoxication.

Amino Acids↗
PubMed1984

Influence of octanoate on the rate of oxidative phosphorylation and the associated extramitochondrial ATP/ADP ratios studied with isolated rat liver mitochondria oxidizing pyruvate.

The regulation of oxidative phosphorylation by the extramitochondrial ATP/ADP ratio was investigated with pyruvate (malate) or pyruvate (malate) plus octanoate as substrates in experiments with isolated rat liver mitochondria. Steady states in the supply of non-saturating substrate concentrations and the activity of oxidative phosphorylation were adjusted by means of a perifusion technique which is based on immobilisation of mitochondria on glass filters. Michaelis-Menten parameters of the pyruvate oxidation in active state respiration were determined both in the absence and presence of octanoate. Octanoate yielded only slight Km value increase, whereas the maximal rate of pyruvate oxidation was diminished to one half. Therefore, it is concluded that the inhibitory action of octanoate on pyruvate oxidation comes close to a non-competitive mechanism. The inhibitory effect of octanoate is completely reversible. When a change in substrate supply was accomplished by substituting pyruvate (malate) plus octanoate for pyruvate (malate) under conditions of a simulated extramitochondrial energy demand, respiration was stimulated and ATP/ADP ratios generated outside mitochondria were shifted to a higher value. Two different responses of the mitochondrial respiration to the extramitochondrial ATP/ADP ratios were found as a function of the presence or absence of octanoate.

Adenosine Diphosphate↗