Brain Pyruvate Dehydrogenase Complex Research Articles

Pyruvate Dehydrogenase Complex in Neonatal Hypoxic-Ischemic Brain Injury.

The disruption of cerebral energy metabolism in relation to brain damage has been the subject of extensive research. However, the pyruvate dehydrogenase complex (PDHC), which is primarily characterized by poor cerebral energy metabolism following brain trauma, has received relatively little study in comparison to newborn hypoxic-ischemic brain injury. Mitochondrial PDHC, a multienzyme complex that functions as a crucial hub in energy metabolism and acts as a central metabolic node to mediate pyruvate oxidation after glycolysis and fuel the Krebs cycle to meet energy demands, has been reported to be one cause of energy metabolism dysfunction according to recent studies. Here we assess the potential mechanisms of neonatal hypoxic-ischemic brain injury-related brain dysfunction mediated by PDHC and further discuss the neuroprotective effects of therapeutic medicines that target PDHC activation. We also provide a summary of recent research on medicines that target PDHC in neonates with hypoxic-ischemic brain damage. Through an understanding of the mechanisms by which it is modulated and an investigation of the neuroprotective techniques available to activate brain PDHC and improve neonatal hypoxic-ischemic impairment, our review emphasizes the significance of PDHC impairment in neonatal hypoxic-ischemic brain injury.

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293.

Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation.

(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia.

In dementia of Alzheimer type (DAT), cerebral glucose metabolism is reduced in vivo, and enzymes involved in glucose breakdown are impaired in post-mortem brain tissue. Pyruvate dehydrogenase complex activity (PDHc) is one of the enzymes known to be reduced, while succinate dehydrogenase activity (SDH), another enzyme of oxidative glucose metabolism is unchanged. In dementia of vascular type (DVT), variable changes in glucose metabolism have been demonstrated in vivo, while changes of enzyme activities in post-mortem brain tissue are unknown. Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Pick's disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue. PDHc in DAT and DVT, but not in Pick's disease was reduced. PDHc activity could be slightly stimulated by 10 micro M of the physiological stereoisomer (r)-alpha-lipoic acid, in controls and DVT (possibly also in Pick's disease), but not in DAT. In all groups investigated SDH was activated by 100 micro M and 1 mM of both isomers of alpha-lipoic acid, whereas 10 mM of both stereoisomers of alpha-lipoic acid caused an inhibition of both, PDHc and SDH activity. The loss of basal and of (r)-alpha-lipoic acid stimulated PDHc activity indicate that a functional or structural impairment of PDHc may exist in DAT and DVT which is not merely attributable to loss of mitochondria since basal and stimulated SDH activities are similar in controls, DVT and DAT, thus indicating selective vulnerability of PDHc.

Functional regulation of brain pyruvate dehydrogenase: Postnatal development, anesthesia and food-deprivation

Abstract The activity of brain pyruvate dehydrogenase complex (PDHC), is regulated by reversible phosphorylation of the alpha subunit of the E1 component (pyruvate dehydrogenase, EC 1.2.4.1) of PDHC. Using an in vitro back-titration assay, we have evaluated the postnatal development of E1α phosphorylation, as well as the effects of acute pentobarbital administration and food-deprivation on cerebral cortical E1α phosphorylation in synaptosomal and free mitochondrial compartments of the albino rat. Between birth and postnatal day 25, the back-titration phosphorylation increased ca 4-fold, with the largest increase occurring between days 15 and 20. The phosphorylation of E1α in the synaptosomal, but not free mitochondrial fraction, was decreased during pentobarbital anesthesia. Following 72 h of food-deprivation, E1α phosphorylation was decreased in both subcellular fractions. The postnatal increase in E1α back-titration phosphorylation is consistent with and similar in magnitude to previously reported increases in the specific enzymatic activity of PDHC. These results also highlight the potential importance of localized subcellular alterations in mitochondrial metabolism and further validate the back-titration phosphorylation of E1α as a valuable tool for the study of central nervous system PDHC metabolism.

Changes in pyruvate dehydrogenase complex (PDHc) activity and [3H]QNB-receptor binding in rat brain subsequent to intracerebroventricular injection of bromopyruvate

Pyruvate dehydrogenase complex (PDHc), a link between carbohydrate and acetylcholine metabolism, is a regulatory enzyme for glucose and neurotransmitter metabolism in the brain and is reduced in Alzheimer-diseased brain. To study functional consequences of an inhibition of PDHc on muscarinic receptor binding, bromopyruvate, a suicide inhibitor od PDHc, was injected intracerebroventricularly (icv) in rats. Bromopyruvate caused a reduction of PDHc activity in the 3 brain regions examined, however, reaching significance only in the cerebral cortex and the hippocampus and not in the striatum, 24 h after injection. 3, 6, and 12 weeks later, there was a normalization or transiently increased activity, respectively, of PDHc in these brain regions. No changes in concentrations of energy-rich phosphates could be demonstrated in the cerebral cortex 12 weeks after brompyruvate injection. The number of muscarinic receptors was significantly reduced in the cerebral cortex 12 weeks after injection. The data indicate that a transient reduction of brain PDHc activity in vivo is associated with a long-lasting reduction in muscarinic cholinergic receptors. Because comparable changes of PDHc and muscarinic receptors are found in dementia of Alzhemier type, the model of bromopyruvate inhibition of PDHc in rats is suggested to be useful for experimental dementia research.

Behavioral deficits persist into old age after inhibition of brain pyruvate dehydrogenase complex (PDHc) in rats—a model of dementia?

Behavioral deficits persist into old age after inhibition of brain pyruvate dehydrogenase complex (PDHc) in rats—a model of dementia?

Variations of brain pyruvate dehydrogenase complex (PDHc) activity after inhibition with bromopyruvate in rats—a model of dementia?

Variations of brain pyruvate dehydrogenase complex (PDHc) activity after inhibition with bromopyruvate in rats—a model of dementia?

Inhibition of rat brain pyruvate dehydrogenase by thiamine analogs

The effects of thiamine thiazolone (TT) and thiamine thiazolone pyrophosphate (TTPP) on the in vitro and in vivo inhibition of pyruvate dehydrogenase complex (PDHC) from rat cortex and hippocampus were characterized. TTPP decreased PDHC activity in vitro but had no effect in vivo following its direct chronic administration via osmotic mini-pumps into the brains of behaving rats. In contrast, TT had no direct effect in vitro following a differential centrifugation purification of the mitochondrial PDHC fraction, but decreased PDHC activity in vivo. Additional experiments demon- strated that the cytosolic fraction converted TT to TTPP which, in turn, inhibited PDHC in vitro. A mechanism is proposed to explain these effects that is consistent with a non-competitive inhibition of brain PDHC by TTPP.

32. Behavioral changes in rats of different ages after in vivo inhibition of brain pyruvate dehydrogenase complex (PDHc)

The second part of the manuscript presents a one-dimensional axisymmetric plane strain model to study lithium insertion induced stresses in different types of silicon nanostructures, – nanowire (Si NW), nanotube (Si NT) and core/shell (Si C/S) nanostructures. The 1-d plane strain model is the dimensionally reduced form of the 2-d model presented in part I. Simulation results from the 1-d plane strain model is compared to the results from the 2-d model for the Si NW. Each of these structures poses a different type of boundary conditions and the stress evolution due to diffusion in each of the cases are discussed. Simulation results indicate that Si NT structures develop lower tensile stresses compared to Si NW structures under similar current densities. Case studies on Si NT for different values of inner to outer radii ratio are also presented. Furthermore, simulations reveal that the Si C/S structures develop much higher stresses (closer to the core/shell interface) compared to Si NW or Si NT, owing to the different expansion factors of the core and shell material.

Evidence that a 41,000 dalton brain phosphoprotein is pyruvate dehydrogenase

Phosphorylation of a brain protein of M r=41,000, termed band F 2, is selectively regulated by effectors of pyruvate dehydrogenase kinase (pyruvate, dichloroacetate, NAD, NADH, CoA, and acetyl CoA). Subcellular fractionation studies indicate a mitochondrial localization of a phosphoprotein with this molecular weight. The phosphorylated α-subunit of purified bovine kidney pyruvate dehydrogenase comigrates with band F 2 on polyacrylamide gels and both appear as a doublet band of M r=41,000−42,000. On the basis of similar regulatory properties, subcellular location and electrophoretic mobility, we propose that band F 2 is the α-subunit of the brain pyruvate dehydrogenase complex. Because band F 2 can be affected by physiological and behavioral treatments, our hypothesis suggests a potential regulatory role for pyruvate dehydrogenase in brain function.

“NEAR-MISS” SUDDEN INFANT DEATH SYNDROME (SIDS) WITH I-ACTIC ACIDOSIS

A healthy 5 mo. old male had six apneic spells with cyanosis and loss of tone, lasting up to 60 seconds, within two days. Although monitored and free of further apneic episodes, hyperlactatemia (46 mg%) was present two and four days later, pyruvate 2.2 mg%, arterial and CSF lactate 43 and 20 mg%; uric acid 11 mg%, plasma alanine increased, urine screen by GC for organic acids normal. Multiple FBS determinations, glucose tolerance and alanine loads were normal and not associated with lactate elevation. Conversion of I-14C pyruvate to 14CO2, measured in WBC and cultured fibroblasts was normal. BMR was normal. On anticonvulaants and thiamine there were 7 more episodes in 6 weeks. Multiple EEC's were normal except for one episode of seizure discharges following 10 second apnea. Spontaneous panting episodes occurred prior to and throughout observation. Following a ketogenic diet with medium chain triglycerides, serum lactate declined gradually to 8.5 mg% and lactate pyruvate ratio normalized: 11. The patient who excretes large amounts of medium chain dlcarboxylic acids, has been asymptomatic for 5 months. A causal relationship with the apparent recovery is possible. The above tests do not suggest defective gluconeogenesis; defective pyruvate dehydrogenase complex in brain is unlikely in view of normal pyruvate metabolism in WBC and fibroblasts, and lower lactate levels in CSF than blood. Lactate, which may be elevated due to dysregulation of respiratory drive, should be monitored in infants at risk for SIDS.

Further studies on the components of lactic dehydrogenase of cerebral cortex.

Journal of NeurochemistryVolume 9, Issue 3 p. 313-320 FURTHER STUDIES ON THE COMPONENTS OF LACTIC DEHYDROGENASE OF CEREBRAL CORTEX* L. B. Flexner, L. B. Flexner Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa.Search for more papers by this authorG. de la Haba, G. de la Haba Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa.Search for more papers by this authorJ. B. Flexner, J. B. Flexner Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa. We are obliged to Miss Sophie Wysienska for technical assistanceSearch for more papers by this author L. B. Flexner, L. B. Flexner Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa.Search for more papers by this authorG. de la Haba, G. de la Haba Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa.Search for more papers by this authorJ. B. Flexner, J. B. Flexner Department of Anatomy and Institute of Neurological Sciences, School of Medicine, University of Pennsylvania, Philadelphia 4, Pa. We are obliged to Miss Sophie Wysienska for technical assistanceSearch for more papers by this author First published: May 1962 https://doi.org/10.1111/j.1471-4159.1962.tb09454.xCitations: 5 * This investigation was supported by research grants B-514 and RG-6970 from the National Institute of Neurological Diseases and Blindness and Division of General Medical Sciences, Public Health Service. AboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume9, Issue3May 1962Pages 313-320 RelatedInformation RecommendedDifferentiation of Leuconostoc species by nicotinamide adenine dinucleotide-dependent d(−)-lactic dehydrogenase profilesL.M.T. Dicks, H.J.J. Van Vuuren, FEMS Microbiology LettersStudies on the Pyruvate Dehydrogenase Complex in Brain with the Arylamine Acetyltransferase‐Coupled AssayHanna Ksiezak-Reding, John P. Blass, Gary E. Gibson, Journal of NeurochemistryThe striatum and cerebral cortex express different muscarinic receptor mRNAsMark R. Brann, Noel J. Buckley, Tom I. Bonner, FEBS LettersEngineering 2-oxoglutarate dehydrogenase to a 2-oxo aliphatic dehydrogenase complex by optimizing consecutive componentsJoydeep Chakraborty, Natalia S. Nemeria, Xu Zhang, Pradeep R. Nareddy, Michal Szostak, Edgardo Farinas, Frank Jordan, AIChE JournalThyroid hormone regulates oxidative phosphorylation in the cerebral cortex and striatum of neonatal ratsBienvenida Martinez, Pilar Del Hoyo, Miguel Angel Martin, Joaquín Arenas, Ana Perez-Castillo, Angel Santos, Journal of Neurochemistry