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PubMed1989

Time courses of the responses of pyruvate dehydrogenase activities to short-term starvation in diaphragm and selected skeletal muscles of the rat.

In the fed state, the percentages of the pyruvate dehydrogenase complex (PDH) in the active form (PDHa) in diaphragm and a selection of skeletal muscles (adductor longus, soleus, extensor digitorum longus, tibialis anterior, gastrocnemius) ranged from 8% (soleus) to 38% (gastrocnemius). Major decreases in PDHa activities in all of these muscles were observed after 15 h of starvation, by which time activities were less than 40% of the fed values. In general, the response to starvation was observed more rapidly in muscles of high oxidative capacity. The patterns of changes in skeletal-muscle PDH activities during the fed-to-starved transition are discussed in relation to changes in lipid-fuel supply and oxidation.

Animals↗
PubMed1998

Muscle acetyl group availability is a major determinant of oxygen deficit in humans during submaximal exercise.

The delay in skeletal muscle mitochondrial ATP production at the onset of exercise is thought to be a function of a limited oxygen supply. The delay, termed the oxygen deficit, can be quantified by assessing the above baseline oxygen consumption during the first few minutes of recovery from exercise. During submaximal exercise, the oxygen deficit is reflected by the extent of muscle phosphocreatine (PCr) breakdown. In the present study, nine male subjects performed 8 min of submaximal, single leg knee extension exercise after saline (Control) and dichloroacetate (DCA) infusion on two separate occasions. Administration of DCA increased resting skeletal muscle pyruvate dehydrogenase complex activation status threefold (Control = 0.4 +/- 0.1 vs. DCA = 1.3 +/- 0.1 mmol acetyl-CoA.min-1.kg wet muscle-1 at 37 degrees C, P < 0.01) and elevated acetylcarnitine concentration fivefold (Control = 2.2 +/- 0.5 vs. DCA = 10.9 +/- 1.2 mmol/kg dry mass, P < 0.01). During exercise, PCr degradation was reduced by approximately 50% after DCA (Control = 33.2 +/- 7.1 vs. DCA = 18.4 +/- 7.1 mmol/kg dry mass, P < 0.05). It would appear, therefore, that in humans acetyl group availability is a major determinant of the rate of increase in mitochondrial respiration at the onset of exercise and hence the oxygen deficit.

Acetylation↗
PubMed1998

Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise.

We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883). This was thought to be a consequence of dichloroacetate increasing acetyl group availability early during contraction. In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia. On two separate occasions (control-saline or dichloroacetate infusion), nine subjects performed 8 min of single-leg knee extension exercise at an intensity aimed at achieving volitional exhaustion in approximately 8 min. During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduces blood flow by approximately 20%. Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold. After 3 min of exercise, phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after dichloroacetate pretreatment, when compared with control conditions. However, after 8 min of exercise no differences existed between treatments. Therefore, it would appear that dichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does not alter the metabolic profile when a maximal effort is approached.

Acetylcarnitine↗
PubMedDate not supplied

MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect.

MR studies were correlated with biochemical results in nine children who presented with lactic acidosis and/or abnormal MR findings in the basal ganglia. Neurologic development was delayed in all nine children. Seven of these patients were diagnosed as having subacute necrotizing encephalomyelopathy (SNE, or Leigh syndrome) on the basis of history, clinical findings, and biochemical studies; of the remaining two, one had congenital lactic acidosis and the other had familial bilateral striatal necrosis with no known biochemical correlate. Although the clinical presentation of these patients was similar, we found distinctive MR abnormalities in characteristic locations in the seven patients with SNE, with or without detectable specific mitochondrial enzyme deficiency in cultured skin fibroblast assays. In our case studies of SNE patients with detectable enzyme deficiency states, defects in pyruvate dehydrogenase complex and cytochrome c oxidase have been found. The MR finding of note in SNE is the remarkably symmetrical involvement, most frequently of the putamen. In our study, lesions were also commonly found in the globus pallidus and the caudate nucleus, but never in the absence of putaminal abnormalities. Other areas of involvement included the paraventricular white matter, corpus callosum, substantia nigra, decussation of superior cerebellar peduncles, periaqueductal region, and brainstem. In patients who present with lactic acidosis and whose MR findings show symmetrical abnormalities in the brain, but with sparing of the putamen, the diagnosis of SNE is in doubt.

Acidosis, Lactic↗
PubMed1993

Anti-idiotype antibodies to anti-mitochondrial antibodies in the sera of patients with primary biliary cirrhosis.

Idiotype-anti-idiotype interactions were investigated in the sera of patients with primary biliary cirrhosis (PBC), which is characterized by the presence of circulating anti-mitochondrial antibodies (AMA). A mouse monoclonal antibody, CPZ674, has been raised to the E2 component of the pyruvate dehydrogenase complex (PDC), which is the target antigen of AMA. CPZ674 recognizes one of the epitopes recognizable by AMA, as demonstrated by competitive Western blotting. Anti-idiotypic antibodies in PBC sera were detected either by their specific binding to CPZ674 in an ELISA or by the formation of idiotype-anti-idiotype complexes with CPZ674, detected using chromatography on a Sephacryl-300 column and by a polyethylene glycol precipitation method. The specificity of the anti-idiotypic antibodies to AMA was shown by their ability to inhibit the binding of AMA to PDC, but not the binding of other autoantibodies to their relevant autoantigens. We have therefore produced evidence for the existence of idiotype-anti-idiotype interactions in PBC, but whether these anti-idiotypic antibodies are involved in the control of AMA is unknown.

Animals↗
PubMed1999

[Severe anorexia in infants in Reunion: a new autosomal recessive disease?].

BACKGROUND: Infantile anorexia is usually considered as a psychogenic disorder with benign prognosis. However, unusually severe characteristics of infantile anorexia, seen in the south of the island, seem to us in favor of a new metabolic etiology. POPULATION AND METHODS: Among 38 known cases, we retrospectively studied the best documented observations of 24 children admitted over the last 25 years to our institution. RESULTS: The sex ratio was ten females and 14 males. Twenty-three of the 24 infants lived in formerly isolated localities of the island where other hereditary diseases have been observed with an unusually high frequency. The family pedigrees favoured an autosomal recessive heredity. Severe anorexia, accompanied by irrepressible vomiting (91%), appeared at the age of 8.5 months +/- 3.5. Parenteral (54.2%) or enteral (54.2%) feeding was necessary but did not always avoid death, which occurred in 45.8% of the cases at the age of 24 months +/- 3.5. All of the children which survived had neurological disorders (pyramidal syndrome, ataxia, laryngeal palsy, mental retardation, seizures) which occurred sometimes at an early stage. The investigations did not allow the identification of any known cause. DISCUSSION: The elevated level of lactic acid in the cerebral spinal fluid seemed to indicate a possible mitochondrial disorder, eventually a mutation of an autosomal gene of the pyruvate dehydrogenase complex because of the normal lactate/pyruvate ratio, but enzymatic activities were normal. The cerebral MRI showed features of leukodystrophy. On the other hand, the elevated level of plasma serotonin seemed to indicate a disorder of the serotonin metabolism, for which an animal model exists. CONCLUSION: We propose to name this new syndrome by the acronym 'RAVINE' which associates Reunion, Anorexia, Vomiting which is Irrepressible, and Neurological signs. Linkage study might allow the localization and isolation of a gene and allow one to start understanding the biological mechanism which we suspect to be an hereditary neurobiological eating disorder.

Anorexia↗
PubMed2002

The immunology of primary biliary cirrhosis: the end of the beginning?

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B-cell and T-cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti-PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti-PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self-antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra-hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.

Animals↗
PubMed1990

MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect.

MR studies were correlated with biochemical results in nine children who presented with lactic acidosis and/or abnormal MR findings in the basal ganglia. Neurologic development was delayed in all nine children. Seven of these patients were diagnosed as having subacute necrotizing encephalomyelopathy (SNE, or Leigh syndrome) on the basis of history, clinical findings, and biochemical studies; of the remaining two, one had congenital lactic acidosis and the other had familial bilateral striatal necrosis with no known biochemical correlate. Although the clinical presentation of these patients was similar, we found distinctive MR abnormalities in characteristic locations in the seven patients with SNE, with or without detectable specific mitochondrial enzyme deficiency in cultured skin fibroblast assays. In our case studies of SNE patients with detectable enzyme deficiency states, defects in pyruvate dehydrogenase complex and cytochrome c oxidase have been found. The MR finding of note in SNE is the remarkably symmetrical involvement, most frequently of the putamen. In our study, lesions were also commonly found in the globus pallidus and the caudate nucleus, but never in the absence of putaminal abnormalities. Other areas of involvement included the paraventricular white matter, corpus callosum, substantia nigra, decussation of superior cerebellar peduncles, periaqueductal region, and brainstem. In patients who present with lactic acidosis and whose MR findings show symmetrical abnormalities in the brain, but with sparing of the putamen, the diagnosis of SNE is in doubt.

Acidosis, Lactic↗
PubMed1993

Mechanisms involved in the coordinate regulation of strategic enzymes of glucose metabolism.

In this review, we evaluate the relative regulatory importance of specific strategic enzymes (in particular glycogen synthase, acetyl-CoA carboxylase [ACC] and the pyruvate dehydrogenase complex [PDH]) for carbohydrate utilization as an anabolic precursor and as an energy substrate during the nutritional transitions between the fed and fasted states. The involvement of the specific protein kinases contributing to the inactivation of these enzymes by phosphorylation [cyclic AMP-dependent protein kinase, AMP-activated protein kinase and PDH kinase] in achieving each regulatory response is also assessed. We demonstrate a striking temporal correlation between hepatic glycogen mobilization and PDH and ACC inactivation by phosphorylation during the immediate postabsorptive period; in contrast, rates of hepatic glycogen synthesis and PDH and ACC expressed activities do not change in parallel during refeeding. The results are consistent with shifting of the primary sites of control for overall hepatic carbon flux during the fed-to-starved and starved-to-fed nutritional transitions achieved, at least in part, by a complex pattern of regulation by protein phosphorylation and metabolites which is critically dependent on the precise nutritional status. Data are also presented that demonstrate asynchronous suppression of glucose uptake/phosphorylation and pyruvate oxidation in cardiac and skeletal muscle during progressive starvation. Analogous asynchrony is observed in the reactivation of these processes in cardiac and skeletal muscle during refeeding after starvation. We provide evidence in support of the concept that selective suppression of pyruvate oxidation in oxidative muscles during early starvation and during the initial phase of refeeding is achieved because of differential sensitivity of glucose uptake/phosphorylation and pyruvate oxidation to lipid-fuel utilization. We discuss the relative importance of regulatory events governing local fatty acid production and utilization (via lipoprotein lipase and carnitine palmitoyltransferase 1, respectively) or overall fatty acid supply (dictated by events at the adipocyte) for fuel utilization by muscle during nutritional transitions. Finally, we assess the regulatory importance of glycogen synthesis in determining overall rates of glucose clearance by skeletal muscle during alimentary hyperglycemia and hyperinsulinemia.

Acetyl-CoA Carboxylase↗
PubMed2000

Histidine modifying agents abolish pyruvate dehydrogenase kinase activity.

Pyruvate dehydrogenase kinase (PDK) specifically phosphorylates the E1alpha subunit of the pyruvate dehydrogenase complex (PDC). Sequence analysis of cloned PDKs led to the proposal that they are mechanistically related to prokaryotic 2-component His-kinases. The reaction mechanism of protein His-kinases involves autophosphorylation of a specific His residue followed by phosphotransfer to an Asp residue. Treatment of recombinant Arabidopsis thaliana PDK with the His-directed reagents diethyl pyrocarbonate (DEPC) and dichloro-(2,2':6', 2"-terpyridine)-platinum(II) dihydrate led to a marked inhibition of autophosphorylation. In addition, DEPC treatment abolished the ability of PDK to trans-phosphorylate and inactivate PDC. These results validate the prediction that PDKs require His residues for activity.

Arabidopsis↗
PubMed1991

An automated microassay for enzyme inhibitory effects of M2 antibodies in primary biliary cirrhosis.

In primary biliary cirrhosis (PBC), autoantibodies are produced to the M2 group of mitochondrial antigens, of which a major constituent is the E2 subunit of the pyruvate dehydrogenase complex (PDC). These antibodies, in addition to conventional reactivities with PDC, characteristically inhibit the catalytic function of PDC in vitro, as judged by a macroinhibition assay based on spectrophotometry. We describe a microinhibition assay adapted for microtitre plates and for an automated readout of results by an ELISA plate reader. We show that this microassay has a sensitivity similar to that of the macroassay. In a study of 83 sera, from PBC and other diseases, the inhibitory microassay proved specific for PBC. This automated inhibitory microassay for PBC-sera could become a primary laboratory procedure for the diagnosis of PBC, particularly because it may identify antibodies to the actual autoepitope on the PDC-E2.

Animals↗
PubMed1992

Isolation and characterization of a new acetate-requiring mutant strain, ace-9, of Neurospora crassa.

A new acetate-requiring mutant strain of Neurospora crassa, ace-9, has been isolated. The mutant gene was mapped between nuc-2 and arg-12 on the right arm of the second linkage group. The ace-9 mutant strain shows very weak activity of pyruvate dehydrogenase complex (PDHC). Three strains that show no activity of PDHC had already been found, i.e., ace-2, ace-3, and ace-4. Thus the ace-9 is the fourth gene that causes the deficiency in PDHC activity by a mutation. Deficiency of PDHC activity in ace-9 strain seems to be due to defective E1 component, because (1) the activity of E1 component enzyme is very weak in ace-9 mutant strain, and (2) normal PDHC activity was resumed when a preparation of ace-9 was mixed with E1-E2 fraction of wild type or with E1 component of wild type E. coli. Difference in thermostability of both E1 component enzyme and PDHC between ace-9 and the wild type strains supports this conclusion.

Acetates↗
PubMed2003

Biochemical and physiological studies of Arabidopsis thaliana transgenic lines with repressed expression of the mitochondrial pyruvate dehydrogenase kinase.

Pyruvate dehydrogenase kinase (PDHK), a negative regulator of the mitochondrial pyruvate dehydrogenase complex (mtPDC), plays a pivotal role in controlling mtPDC activity, and hence, the TCA cycle and cell respiration. Previously, the cloning of a PDHK cDNA from Arabidopsis thaliana and the effects of constitutively down-regulating its expression on plant growth and development has been reported. The first detailed analyses of the biochemical and physiological effects of partial silencing of the mtPDHK in A. thaliana using antisense constructs driven by both constitutive and seed-specific promoters are reported here. The studies revealed an increased level of respiration in leaves of the constitutive antisense PDHK transgenics; an increase in respiration was also found in developing seeds of the seed-specific antisense transgenics. Both constitutive and seed-specific partial silencing of the mtPDHK resulted in increased seed oil content and seed weight at maturity. Feeding 3-(14)C pyruvate to bolted stems containing siliques (constitutive transgenics), or to isolated siliques or immature seeds (seed-specific transgenics) confirmed a higher rate of incorporation of radiolabel into all seed lipid species, particularly triacylglycerols. Neither constitutive nor seed-specific partial silencing of PDHK negatively affected overall silique and seed development. Instead, oil and seed yield, and overall plant productivity were improved. These findings suggest that a partial reduction of the repression of the mtPDC by antisense PDHK expression can alter carbon flux and, in particular, the contribution of carbon moieties from pyruvate to fatty acid biosynthesis and storage lipid accumulation in developing seeds, implicating a role for mtPDC in fatty acid biosynthesis in seeds.

Antisense Elements (Genetics)↗
PubMed1993

Physiological modulation of the uptake and fate of glucose in brown adipose tissue.

Glucose utilization indices (GUI values) and rates of fatty acid synthesis in interscapular brown adipose tissue (IBAT) varied during the diurnal cycle in virgin and late-pregnant rats permitted unrestricted access to food. In virgin rats, peak GUI values and lipogenic rates were observed at the end of the dark (feeding) phase, but were not sustained during the light phase. Whereas peak GUI values were comparable with those observed during re-feeding after 24 h starvation, maximum rates of IBAT fatty acid synthesis in virgin rats during the diurnal cycle were only approx. 25% of those measured during re-feeding after 24 h starvation. Despite hyperphagia, GUI values during the diurnal cycle in late-pregnant rats fed ad libitum were generally lower than those of age-matched virgin controls. The percentage of pyruvate dehydrogenase complex present in the active form (PDHa) was also significantly decreased. Suppression of GUI and PDHa was not parallelled by suppression of fatty acid synthesis. IBAT GUI values in late-pregnant rats during chow re-feeding ad libitum after 24 h starvation were only 25% of those of corresponding virgin controls, and stimulation of fatty acid synthesis was also dramatically attenuated. The suppression of IBAT GUI values after re-feeding in pregnancy was not due to depletion of GLUT 4 protein. The results are discussed in relation to the importance of glucose as a precursor for fatty acid synthesis in IBAT.

Adipose Tissue, Brown↗
PubMed1987

Effects of dichloroacetate on the mechanical function of the isolated ischemic heart.

The effects of sodium dichloroacetate (DCA) on the activity of the pyruvate dehydrogenase complex (PDH) and the mechanical function of the isolated ischemic rat heart were investigated. Ischemia was induced by restriction of coronary flow. Perfusion with DCA caused a decrease in the tension developed (DT) and the maximal rate of tension development (+ dT/dt max), and an increase in the resting tension (RT) at low flow rates (0.6 and 0.15 ml/min). However, it did not affect the DT or +dT/dt max of normoxic hearts (3 ml/min) or hearts at zero flow rate. DCA increased PDH activity in hearts at all flow rates. It was concluded that this effect of DCA was associated with a decrease in lactate production, rather than an increase in the lactate/pyruvate ratio.

Acetates↗
PubMed2000

Depletion of lactate by dichloroacetate reduces cardiac efficiency after hemorrhagic shock.

We have demonstrated previously that dichloroacetate (DCA) treatment in rodents ameliorates, via activation of the pyruvate dehydrogenase complex, the cardiovascular depression observed after hemorrhagic shock. To explore the mechanism of this effect, we administered DCA in a large animal model of hemorrhagic shock. Mongrel hounds were anesthetized with 1.5% isoflurane and were measured for hemodynamics, myocardial contractility, and myocardial substrate utilization. They were hemorrhaged to a mean arterial pressure of 35 mm Hg for 90 min or until arterial lactate levels reached 7.0 mM (1137 +/- 47 mL or 49 +/- 2% total blood volume). Animals were chosen at random to receive DCA dissolved in water or an equal volume of saline at the onset of resuscitation. Two-thirds of the shed blood volume was returned immediately after giving an equivalent volume of saline. Two hours after the onset of resuscitation, mean arterial pressure was not different between DCA and control groups (79 +/- 3 vs. 82 +/- 3 mm Hg, respectively). Arterial lactate levels were significantly reduced by DCA (0.5 +/- 0.06 vs. 2.0 +/- 0.2 mM). However, DCA treatment was associated with a decreased stroke volume index (0.56 +/- 0.06 vs. 0.82 +/- 0.08 mL/kg/beat) and a decreased myocardial efficiency (19 vs. 41 L x mm Hg/mL/100 g tissue). During resuscitation by DCA, myocardial lactate consumption was reduced (21.4 +/- 3.7 vs. 70.7 +/- 16.3 micromole/min/100 g tissue) despite a three-fold increase in myocardial pyruvate dehydrogenase activity, while free fatty acid levels actually began to rise. Although increased lactate oxidation should be beneficial during resuscitation, we propose that DCA treatment led to a deprivation of myocardial lactate supply, which reduced net myocardial lactate oxidation, thus compromising myocardial function during resuscitation from hemorrhagic shock.

Acidosis, Lactic↗
PubMed2006

Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I-IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.

Acetyl Coenzyme A↗
PubMed1990

The gene for the alpha polypeptide of pyruvate dehydrogenase is X-linked in humans.

The chromosomal location of the gene for the alpha polypeptide of the pyruvate dehydrogenase (alpha E1), a major component of the pyruvate dehydrogenase complex, was determined by using a cloned cDNA for alpha E1. This 1-kb cDNA was isolated from a human liver lambda gt11 expression library with specific antibodies and included the coding (from amino acid 144 to the carboxy terminus) and the 3' untranslated regions. Southern blot analysis of the DNA from a panel of rodent-human hybrid cells showed that the absence or the presence of the major EcoRI fragment that hybridized with this cDNA probe was concordant with the presence of the Xq24-p22 region of the human X chromosome. The result of in situ hybridization with human metaphase chromosomes further mapped the alpha E1 gene to the Xp arm.

Antibodies↗