Role Of Pyruvate Dehydrogenase Complex Research Articles

The Role of the Pyruvate Dehydrogenase Complex in the Development of Ischemic-Reperfusion Syndrome

Background. One of the key components of energy metabolism is the pyruvate dehydrogenase complex (PDC), the activity of which can be targeted by some cytoprotectors. However, their role remains unclear. It is known that the activation of the PDC in tumor cells leads to an inversion of anaerobic glycolysis with an increase in the generation of free radicals in the respiratory chain and a decrease in viability. At the same time, there is evidence of increased resistance of normal cells to hypoxia and reperfusion.Objectives. Analysis of current information on the role of PDC in the development of pathologic biochemical changes in ischemic reperfusion syndrome and methods of metabolic correction using agents for regulating the activity of the considered multienzyme complex. Methods. The bibliographical search was carried out across the eLIBRARY and PubMed databases with a selection of articles published over the past 10 years in the English and Russian languages, as well as some parts of fundamental works in the selected field, published more than 10 years. To be selected for bibliographical review, the article can be of any design, reflecting the ideas about the role of PDC in the development of pathologic biochemical changes in ischemic-reperfusion lesions of various organs and tissues.Results. The bibliographical analysis indicates a decrease in the activity of PDC in myocardial tissue during a heart attack or heart failure, the activity of the enzyme in skeletal muscles decreases against the background of acute hypoxia. PDC activity also decreases under chronic stress and extensive muscular exercise. At the same time, the PDC activity remains at the normal level in the ischemic period, and the transition to the reperfusion period is accompanied by a sharp decrease in the activity of the multienzyme complex. The PDC inactivation occurring under these conditions can result from a damage by reactive oxygen species, as well as by regulatory control changes through phosphorylation/dephosphorylation. Assuming the key role of PDC in the development of energy exchange disorders against the ischemic-reperfusion injuries 2 main strategies might be offered for metabolic correction: 1) an increase in the activity of PDC (activator — sodium dichloroacetate) or compensation for its lack with substrates of the tricarboxylic acids (acetylcarnitine, β-ydroxybutyrate); 2) protection of PDC from damage (antioxidants).Conclusion. The basis of energy exchange disorders in the reperfusion period is a decrease in PDC activity, and modification of its activity is a promising direction for metabolic prevention or correction of ischemic-reperfusion injures.

Analysis of the Growth and Metabolites of a Pyruvate Dehydrogenase Complex- Deficient Klebsiella pneumoniae Mutant in a Glycerol-Based Medium.

To determine the role of pyruvate dehydrogenase complex (PDHC) in Klebsiella pneumoniae, the growth and metabolism of PDHC-deficient mutant in glycerol-based medium were analyzed and compared with those of other strains. Under aerobic conditions, the PDHC activity was fourfold higher than that of pyruvate formate lyase (PFL), and blocking of PDHC caused severe growth defect and pyruvate accumulation, indicating that the carbon flux through pyruvate to acetyl coenzyme A mainly depended on PDHC. Under anaerobic conditions, although the PDHC activity was only 50% of that of PFL, blocking of PDHC resulted in more growth defect than blocking of PFL. Subsequently, combined with the requirement of CO2 and intracellular redox status, it was presumed that the critical role of PDHC was to provide NADH for the anaerobic growth of K. pneumoniae. This presumption was confirmed in the PDHC-deficient mutant by further blocking one of the formate dehydrogenases, FdnGHI. Besides, based on our data, it can also be suggested that an improvement in the carbon flux in the PFL-deficient mutant could be an effective strategy to construct highyielding 1,3-propanediol-producing K. pneumoniae strain.

Featured Article: Beta cell specific pyruvate dehydrogenase alpha gene deletion results in a reduced islet number and β-cell mass postnatally

The ability of pancreatic β-cells to undertake glucose-stimulated insulin secretion (GSIS) depends on the generation of adenosine triphosphate (ATP) within the mitochondria from pyruvate, a major rate-limiting enzyme being pyruvate dehydrogenase (PDH) complex (PDC). However, glucose metabolism also controls β-cell mass. To examine the role of PDC in the regulation of pancreatic β-cell development and maturation, we generated β-cell-targeted PDHα subunit knock-out male mice (β-PDHKO) and compared these with control males (β-PDHCT) from birth until 6-8 weeks age. Pancreas morphology, transcription factor expression, pancreatic insulin content, and circulating glucose and insulin values were compared. Compared to β-PDHCT male mice, β-PDHKO animals had significantly reduced pancreatic insulin content from birth, a lower serum insulin content from day 15, and relative hyperglycemia from day 30. Isolated islets from β-PDHKO mice demonstrated a reduced GSIS. The number of islets per pancreatic area, mean islet area, and the proportion of islet cells that were β-cells were all reduced in β-PDHKO animals. Similarly the number of insulin-immunopositive, extra-islet small endocrine cell clusters, a possible source of β-cell progenitors, was lower in β-PDHKO mice. Analysis of pancreatic expression of transcription factors responsible for β-cell lineage commitment, proliferation, and maturation, Pdx1, Neurogenin3, and NeuroD1 showed that mRNA abundance was reduced in the β-PDHKO. This demonstrates that PDC is not only required for insulin expression and glucose-stimulated secretion, but also directly influences β-cell growth and maturity, and positions glucose metabolism as a direct regulator of β-cell mass and plasticity.

Basal and insulin‐stimulated pyruvate dehydrogenase complex activation, glycogen synthesis and metabolic gene expression in human skeletal muscle the day after a single bout of exercise

The role of pyruvate dehydrogenase complex (PDC) in insulin-stimulated glycogen replenishment the day after exercise, and its molecular control, has not been examined. This study investigated the effect of acute exercise on basal and insulin-stimulated PDC activity (the rate-limiting step in glucose oxidation), glycogen synthesis and the expression of metabolic genes and transcription factors associated with changes in PDC activation and glucose metabolism. Eight healthy men (age 24 +/- 2 years, body mass 79 +/- 4 kg) underwent a euglycaemic, hyperinsulinaemic clamp 22 h after 90 min of one-legged cycling at 60% maximal oxygen consumption. Skeletal muscle glycogen content was similar in the exercised (EX) and non-exercised leg (CON) preclamp (471 +/- 30 versus 463 +/- 50 mmol (kg dry matter)(1), respectively) but increased during the clamp in EX to 527 +/- 20 mmol (kg dry matter)(1), such that it was 17% greater than in CON (449 +/- 35 mmol (kg dry matter)(1), P < 0.05). This increase in insulin-mediated glycogen storage was independent of insulin-stimulated Akt serine(473) phosphorylation and activation of PDC. Prior exercise did not modulate the mRNA expression and protein content of pyruvate dehydrogenase kinase 4 (PDK4) in skeletal muscle, but was associated with increased hexokinase II mRNA expression and protein content and upregulation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1alpha (PGC1alpha) and PPARdelta gene expression. Collectively, these findings suggest that prior exercise does not alter basal and insulin-stimulated PDC activation and the protein content of PDK4 the following day, but is associated with increased capacity (through upregulation of hexokinase II content) of muscle to phosphorylate and divert glucose towards glycogen storage.

Role of pyruvate dehydrogenase complex in traumatic brain injury and Measurement of pyruvate dehydrogenase enzyme by dipstick test

Objectives:The present study was designed to investigate the role of a mitochondrial enzyme pyruvate dehydrogenase (PDH) on the severity of brain injury, and the effects of pyruvate treatment in rats with traumatic brain injury (TBI).Methods:We examined rats subjected to closed head injury using a fluid percussion device, and treated with sodium pyruvate (antioxidant and substrate for PDH enzyme). At 72 h post injury, blood was analyzed for blood gases, acid-base status, total PDH enzyme using a dipstick test and malondialdehyde (MDA) levels as a marker of oxidative stress. Brain homogenates from right hippocampus (injured area) were analyzed for PDH content, and immunostained hippocampus sections were used to determine the severity of gliosis and PDH E1-∞ subunit.Results:Our data demonstrate that TBI causes a significant reduction in PDH enzyme, disrupt-acid-base balance and increase oxidative stress in blood. Also, lower PDH enzyme in blood is related to the increased gliosis and loss of its PDH E1-∞ subunit PDH in brain tissue, and these effects of TBI were prevented by pyruvate treatment.Conclusion:Lower PDH enzyme levels in blood are related to the global oxidative stress, increased gliosis in brain, and severity of brain injury following TBI. These effects can be prevented by pyruvate through the protection of PDH enzyme and its subunit E-1.

Metabolic acidosis inhibits pyruvate oxidation in chick liver by decreasing activity of pyruvate dehydrogenase complex

Replacement of drinking water with NH 4Cl (1.5%) solution significantly reduced blood pH on the 2nd d in chicks and thereafter. Concomitant with this reduction, oxidation rate of state 3 with pyruvate in liver mitochondria was also decreased in acidotic animals when compared with control animals. No significant differences between the two groups were observed in the state 4 oxidation at any feeding period. The ADP O ratio did not appear to be affected by the treatment. The successive experiments of gavage-feeding for 4 d were also employed to ensure an equivalent intake of diet and the amount of NH 4Cl given. As a result, the higher the NH 4Cl provided, the lower the oxidation rate of state 3 with pyruvate in liver mitochondria, and the actual activity of pyruvate dehydrogenase complex, as expressed as units of produced CO 2 per g wet weight of liver, which were accompanied by the lower pH in blood. This study provides the first evidence for a critical role of pyruvate dehydrogenase complex in the regulation of pyruvate catabolism in the liver from acidotic chicks induced by NH 4Cl.

Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex.

Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 x 10(-4)mM) allows selection of patients with thiamine-responsive lactic acidaemia.