scholarly journals E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity

2016 ◽  
Vol 113 (39) ◽  
pp. 10998-11003 ◽  
Author(s):  
Matthieu Lacroix ◽  
Geneviève Rodier ◽  
Olivier Kirsh ◽  
Thibault Houles ◽  
Hélène Delpech ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Energy Demand ◽  
Clinical Symptoms ◽  
Tricarboxylic Acid Cycle ◽  
Striated Muscles ◽  
Pyruvate Oxidation ◽  
Mitochondrial Pyruvate Carrier ◽  
Lactic Acidemia ◽  
Transcription Factor 1 ◽  
Dihydrolipoyl Dehydrogenase

The mitochondrial pyruvate dehydrogenase (PDH) complex (PDC) acts as a central metabolic node that mediates pyruvate oxidation and fuels the tricarboxylic acid cycle to meet energy demand. Here, we reveal another level of regulation of the pyruvate oxidation pathway in mammals implicating the E4 transcription factor 1 (E4F1). E4F1 controls a set of four genes [dihydrolipoamide acetlytransferase (Dlat), dihydrolipoyl dehydrogenase (Dld), mitochondrial pyruvate carrier 1 (Mpc1), and solute carrier family 25 member 19 (Slc25a19)] involved in pyruvate oxidation and reported to be individually mutated in human metabolic syndromes. E4F1 dysfunction results in 80% decrease of PDH activity and alterations of pyruvate metabolism. Genetic inactivation of murine E4f1 in striated muscles results in viable animals that show low muscle PDH activity, severe endurance defects, and chronic lactic acidemia, recapitulating some clinical symptoms described in PDC-deficient patients. These phenotypes were attenuated by pharmacological stimulation of PDH or by a ketogenic diet, two treatments used for PDH deficiencies. Taken together, these data identify E4F1 as a master regulator of the PDC.

scholarly journals Effect of dexamethasone on gluconeogenesis, pyruvate kinase, pyruvate carboxylase and pyruvate dehydrogenase flux in isolated hepatocytes

1993 ◽  
Vol 289 (3) ◽  
pp. 821-828 ◽  
Author(s):  
C G Jones ◽  
S K Hothi ◽  
M A Titheradge
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Tricarboxylic Acid Cycle ◽  
Acute Effect ◽  
Isolated Hepatocytes ◽  
Pyruvate Oxidation ◽  
Parallel Increase ◽  
Glucose Output

Treatment of 18 h-starved rats with dexamethasone and subsequent isolation and incubation of the hepatocytes in the presence of the steroid increased gluconeogenic flux with both 1.0 mM pyruvate and 1.0 mM lactate plus 0.2 mM pyruvate as the substrate. The magnitude of stimulation was comparable with both substrates. The increase in glucose output was accompanied by an increased flux through pyruvate carboxylase, although the absolute flux and magnitude were considerably less in the presence of the more reduced substrate. The effect of the steroid on the flux through pyruvate dehydrogenase was substrate-dependent, an inhibition occurring with the more oxidized substrate. There was no effect of steroid treatment on [1-14C]lactate or pyruvate oxidation or on tricarboxylic-acid-cycle flux as measured by [3-14C]pyruvate oxidation. Dexamethasone treatment resulted in a parallel increase in both pyruvate kinase flux and glucose synthesis with both substrates employed, indicating that the steroid had no effect on the partitioning of phosphoenolpyruvate between pyruvate and lactate formation and gluconeogenesis. Similarly there was no effect of the steroid on either the activity ratio or the total pyruvate kinase activity in the cells. It is suggested that the acute effect of the dexamethasone to increase gluconeogenesis resides at the level of phosphoenolpyruvate formation, i.e. pyruvate carboxylase and possibly phosphoenolpyruvate carboxykinase.

scholarly journals Malonyl-proteome profiles of Staphylococcus aureus reveal lysine malonylation modification in enzymes involved in energy metabolism

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yanan Shi ◽  
Jingjing Zhu ◽  
Yan Xu ◽  
Xiaozhao Tang ◽  
Zushun Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Energy Metabolism ◽  
Active Sites ◽  
Current Knowledge ◽  
Tricarboxylic Acid Cycle ◽  
Protein A ◽  
Pentose Phosphate ◽  
Post Translational Modification ◽  
Bacterial Physiology ◽  
Dihydrolipoyl Dehydrogenase

Abstract Background Protein lysine malonylation, a novel post-translational modification (PTM), has been recently linked with energy metabolism in bacteria. Staphylococcus aureus is the third most important foodborne pathogen worldwide. Nonetheless, substrates and biological roles of malonylation are still poorly understood in this pathogen. Results Using anti-malonyl-lysine antibody enrichment and high-resolution LC-MS/MS analysis, 440 lysine-malonylated sites were identified in 281 proteins of S. aureus strain. The frequency of valine in position − 1 and alanine at + 2 and + 4 positions was high. KEGG pathway analysis showed that six categories were highly enriched, including ribosome, glycolysis/gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), valine, leucine, isoleucine degradation, and aminoacyl-tRNA biosynthesis. In total, 31 malonylated sites in S. aureus shared homology with lysine-malonylated sites previously identified in E. coli, indicating malonylated proteins are highly conserved among bacteria. Key rate-limiting enzymes in central carbon metabolic pathways were also found to be malonylated in S. aureus, namely pyruvate kinase (PYK), 6-phosphofructokinase, phosphoglycerate kinase, dihydrolipoyl dehydrogenase, and F1F0-ATP synthase. Notably, malonylation sites were found at or near protein active sites, including KH domain protein, thioredoxin, alanine dehydrogenase (ALD), dihydrolipoyl dehydrogenase (LpdA), pyruvate oxidase CidC, and catabolite control protein A (CcpA), thus suggesting that lysine malonylation may affect the activity of such enzymes. Conclusions Data presented herein expand the current knowledge on lysine malonylation in prokaryotes and indicate the potential roles of protein malonylation in bacterial physiology and metabolism.

The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity

2011 ◽  
Vol 111 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Lorenzo K. Love ◽  
Paul J. LeBlanc ◽  
J. Greig Inglis ◽  
Nicolette S. Bradley ◽  
Jon Choptiany ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Endurance Training ◽  
Aerobic Capacity ◽  
Pyruvate Dehydrogenase ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Carbohydrate Oxidation ◽  
Pyruvate Dehydrogenase Phosphatase

Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme responsible for regulating the conversion of pyruvate to acetyl-CoA for use in the tricarboxylic acid cycle. PDH is regulated through phosphorylation and inactivation by PDH kinase (PDK) and dephosphorylation and activation by PDH phosphatase (PDP). The effect of endurance training on PDK in humans has been investigated; however, to date no study has examined the effect of endurance training on PDP in humans. Therefore, the purpose of this study was to examine differences in PDP activity and PDP1 protein content in human skeletal muscle across a range of muscle aerobic capacities. This association is important as higher PDP activity and protein content will allow for increased activation of PDH, and carbohydrate oxidation. The main findings of this study were that 1) PDP activity ( r2 = 0.399, P = 0.001) and PDP1 protein expression ( r2 = 0.153, P = 0.039) were positively correlated with citrate synthase (CS) activity as a marker for muscle aerobic capacity; 2) E1α ( r2 = 0.310, P = 0.002) and PDK2 protein ( r2 = 0.229, P =0.012) are positively correlated with muscle CS activity; and 3) although it is the most abundant isoform, PDP1 protein content only explained ∼18% of the variance in PDP activity ( r2 = 0.184, P = 0.033). In addition, PDP1 in combination with E1α explained ∼38% of the variance in PDP activity ( r2 = 0.383, P = 0.005), suggesting that there may be alternative regulatory mechanisms of this enzyme other than protein content. These data suggest that with higher muscle aerobic capacity (CS activity) there is a greater capacity for carbohydrate oxidation (E1α), in concert with higher potential for PDH activation (PDP activity).

scholarly journals Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise

1976 ◽  
Vol 158 (2) ◽  
pp. 203-210 ◽  
Author(s):  
S A Hagg ◽  
S I Taylor ◽  
N B Ruberman
Keyword(s):  
Skeletal Muscle ◽  
Dehydrogenase Activity ◽  
Pyruvate Dehydrogenase ◽  
Preceding Paper ◽  
Diabetic Rats ◽  
Pyruvate Dehydrogenase Kinase ◽  
Lactate Oxidation ◽  
Pyruvate Oxidation ◽  
Measured Activity ◽  
Exercise Induced

1. The interconversion of pyruvate dehydrogenase between its inactive phosphorylated and active dephosphorylated forms was studied in skeletal muscle. 2. Exercise, induced by electrical stimulation of the sciatic nerve (5/s), increased the measured activity of (active) pyruvate dehydrogenase threefold in intact anaesthetized rated within 2 min. No further increase was seen after 15 min of stimulation. 3. In the perfused rat hindquarter, (active) pyruvate dehydrogenase activity was decreased by 50% in muscle of starved and diabetic rats. Exercise produced a twofold increase in its activity in all groups; however, the relative differences between fed, starved and diabetic groups persisted. 4. Perfusion of muslce with acetoacetate (2 mM) decreased (active) pyruvate dehydrogenase activity by 50% at rest but not during exercise. 5. Whole-tissue concentrations of pyruvate and citrate, inhibitors of (active) pyruvate dehydrogenase kinase and (inactive) pyruvate dehydrogenase phosphate phosphatase respectively, were not altered by excerise. A decrease in the ATP/ADP ratio was observed, but did not appear to be sufficient to account for the increase in (active) pyruvate dehydrogenase activity. 6. The results suggest that interconversion of the phosphorylated and dephosphorylated forms of pyruvate dehydrogenase plays a major role in the regulation of pyruvate oxidation by eomparison of enzyme activity with measurements of lactate oxidation in the perfused hindquarter [see the preceding paper, Berger et al. (1976)] suggest that pyruvate oxidation is also modulated by the concentrations of substrates, cofactors and inhibitors of (active) pyruvate dehydrogenase activity.

scholarly journals 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

2000 ◽  
Vol 346 (3) ◽  
pp. 651-657 ◽  
Author(s):  
Mary C. SUGDEN ◽  
Alexandra KRAUS ◽  
Robert A. HARRIS ◽  
Mark J. HOLNESS
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Cycle ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Anterior Tibialis

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.

scholarly journals Glucose metabolism and its regulation in pieces of perirenal adipose tissue from foetal lambs

1983 ◽  
Vol 210 (3) ◽  
pp. 677-683 ◽  
Author(s):  
J P Robertson ◽  
A Faulkner ◽  
R G Vernon
Keyword(s):  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Glucose Utilization ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Acid Cycle ◽  
Near Term ◽  
Glucose 6 Phosphate Dehydrogenase

1. The following were measured in pieces of perirenal adipose tissue obtained from foetal lambs at about 120 days of gestation or within 3 days of term, and 9-month-old sheep: the rates of synthesis from glucose of fatty acids, acylglycerol glycerol, pyruvate and lactate; the rate of glucose oxidation to CO2 and the proportions contributed by the pentose phosphate cycle, pyruvate dehydrogenase and the tricarboxylic acid cycle; the activities of hexokinase, glucose 6-phosphate dehydrogenase, phosphofructokinase, pyruvate kinase and pyruvate dehydrogenase. 2. The total rate of glucose utilization was lower in pieces of adipose tissue from near-term lambs than 120-day foetal lambs and the pattern of glucose metabolism differed, with, for example, a much smaller proportion of glucose carbon being used for fatty acid synthesis, whereas a greater proportion of glucose oxidation occurred via the tricarboxylic acid cycle in the near-term lambs. In general, these differences in glucose metabolism were not associated with differences in the activities of the various enzymes listed above. 3. The rates of glucose utilization per fat-cell by 120-day foetal lambs and 9-month-old sheep were very similar but, again, the proportions metabolized to the various products differed. In particular, there was a smaller proportion of glucose oxidized via the pentose phosphate cycle and a greater proportion oxidized via pyruvate dehydrogenase and the tricarboxylic acid cycle in adipose tissue from foetal lambs. These differences were matched by a lower activity of glucose 6-phosphate dehydrogenase and a higher pyruvate dehydrogenase activity in fat-cells from the foetal lambs.

scholarly journals The E2 Domain of OdhA of Corynebacterium glutamicum Has Succinyltransferase Activity Dependent on Lipoyl Residues of the Acetyltransferase AceF

2010 ◽  
Vol 192 (19) ◽  
pp. 5203-5211 ◽  
Author(s):  
Melanie Hoffelder ◽  
Katharina Raasch ◽  
Jan van Ooyen ◽  
Lothar Eggeling
Keyword(s):  
Corynebacterium Glutamicum ◽  
Pyruvate Dehydrogenase ◽  
The Other ◽  
Central Metabolism ◽  
Mutant Proteins ◽  
Oxoglutarate Dehydrogenase ◽  
The Individual ◽  
Activity Dependent ◽  
Dihydrolipoyl Dehydrogenase ◽  
Mutant Cells

ABSTRACT Oxoglutarate dehydrogenase (ODH) and pyruvate dehydrogenase (PDH) complexes catalyze key reactions in central metabolism, and in Corynebacterium glutamicum there is indication of an unusual supercomplex consisting of AceE (E1), AceF (E2), and Lpd (E3) together with OdhA. OdhA is a fusion protein of additional E1 and E2 domains, and odhA orthologs are present in all Corynebacterineae, including, for instance, Mycobacterium tuberculosis. Here we show that deletion of any of the individual domains of OdhA in C. glutamicum resulted in loss of ODH activity, whereas PDH was still functional. On the other hand, deletion of AceF disabled both PDH activity and ODH activity as well, although isolated AceF protein had solely transacetylase activity and no transsuccinylase activity. Surprisingly, the isolated OdhA protein was inactive with 2-oxoglutarate as the substrate, but it gained transsuccinylase activity upon addition of dihydrolipoamide. Further enzymatic analysis of mutant proteins and mutant cells revealed that OdhA specifically catalyzes the E1 and E2 reaction to convert 2-oxoglutarate to succinyl-coenzyme A (CoA) but fully relies on the lipoyl residues provided by AceF involved in the reactions to convert pyruvate to acetyl-CoA. It therefore appears that in the putative supercomplex in C. glutamicum, in addition to dihydrolipoyl dehydrogenase E3, lipoyl domains are also shared, thus confirming the unique evolutionary position of bacteria such as C. glutamicum and M. tuberculosis.

scholarly journals Biological function of cobalamin: causes and effects of hypocobalaminemia at the molecular, cellular, tissue and organism level

2020 ◽  
Vol 74 ◽  
pp. 443-451
Author(s):  
Zuzanna Rzepka ◽  
Mateusz Maszczyk ◽  
Dorota Wrześniok
Keyword(s):  
Vitamin B12 ◽  
Biological Function ◽  
Clinical Symptoms ◽  
Tricarboxylic Acid Cycle ◽  
Megaloblastic Anemia ◽  
Vitamin B12 Deficiency ◽  
Cellular Tissue ◽  
Water Soluble ◽  
Cobalamin Deficiency ◽  
Loss Of Function

Cobalamin (vitamin B12) is a complex compound, which is classified as a water-soluble vitamin. Absorption of cobalamin in the gut and its transport to cells is a unique process, in which many proteins are involved. The loss of function of these proteins causes serious cell homeostasis disturbance, which may result in the dysfunction of many tissues and organs. Vitamin B12, a cofactor of methionine synthase, provides methylation process and nucleic acid synthesis. Cobalamin is also necessary for methylmalonyl-CoA mutase activity. The enzyme synthesizes succinyl-CoA, an intermediate in tricarboxylic acid cycle. Vitamin B12 deficiency is an important and current health problem. It may be caused by insufficient dietary intake, age, or disease-related malabsorption and genetic defects of mechanisms involved in the absorption, transport and metabolism of cobalamin. Hypocobalaminemia can also result from long-term pharmacotherapy with medicines: metformin, proton pump inhibitors (e.g. omeprazole) and H2-receptor antagonists (e.g. ranitidine). Significant clinical symptoms of cobalamin deficiency include hematological abnormalities, mainly megaloblastic anemia, as well as neurological disorders resulting from degeneration within the nervous system. Early diagnosis and starting treatment with vitamin B12 increase chances for a complete cure. Therefore, the diagnostically important symptom of hypocobalaminemia may be skin manifestations, mainly hyperpigmentations, but also premature graying of hair. The aim of this review article was to summarize the current state of knowledge on the biological function of cobalamin, as well as the causes and consequences of its deficiency at the molecular, cellular, tissue and organism level.

scholarly journals Dimming the Powerhouse: Mitochondrial Dysfunction in the Liver and Skeletal Muscle of Intrauterine Growth Restricted Fetuses

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander L. Pendleton ◽  
Stephanie R. Wesolowski ◽  
Timothy R. H. Regnault ◽  
Ronald M. Lynch ◽  
Sean W. Limesand
Keyword(s):  
Skeletal Muscle ◽  
Nutrient Availability ◽  
Energy Demand ◽  
Metabolic Diseases ◽  
Tricarboxylic Acid Cycle ◽  
Substrate Utilization ◽  
Nutrient Concentrations ◽  
Metabolic Dysfunction ◽  
Intrauterine Growth ◽  
Fetal Survival

Intrauterine growth restriction (IUGR) of the fetus, resulting from placental insufficiency (PI), is characterized by low fetal oxygen and nutrient concentrations that stunt growth rates of metabolic organs. Numerous animal models of IUGR recapitulate pathophysiological conditions found in human fetuses with IUGR. These models provide insight into metabolic dysfunction in skeletal muscle and liver. For example, cellular energy production and metabolic rate are decreased in the skeletal muscle and liver of IUGR fetuses. These metabolic adaptations demonstrate that fundamental processes in mitochondria, such as substrate utilization and oxidative phosphorylation, are tempered in response to low oxygen and nutrient availability. As a central metabolic organelle, mitochondria coordinate cellular metabolism by coupling oxygen consumption to substrate utilization in concert with tissue energy demand and accretion. In IUGR fetuses, reducing mitochondrial metabolic capacity in response to nutrient restriction is advantageous to ensure fetal survival. If permanent, however, these adaptations may predispose IUGR fetuses toward metabolic diseases throughout life. Furthermore, these mitochondrial defects may underscore developmental programming that results in the sequela of metabolic pathologies. In this review, we examine how reduced nutrient availability in IUGR fetuses impacts skeletal muscle and liver substrate catabolism, and discuss how enzymatic processes governing mitochondrial function, such as the tricarboxylic acid cycle and electron transport chain, are regulated. Understanding how deficiencies in oxygen and substrate metabolism in response to placental restriction regulate skeletal muscle and liver metabolism is essential given the importance of these tissues in the development of later lifer metabolic dysfunction.

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