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Inactivation of pyruvate dehydrogenase complex in heart muscle mitochondria of gold-thioglucose-induced obese mice is not due to a stable increase in activity of pyruvate dehydrogenase kinase.

ABSTRACT: The proportion of pyruvate dehydrogenase (PDH) complex in the active dephosphorylated form was decreased (compared with fed lean control mice) in heart muscle mitochondria after the induction of obesity with gold-thioglucose (by 54%) or starvation of lean mice for 48 h (by 81%). The effects of obesity to inactivate PDH complex were demonstrable 4 weeks after administration of gold-thioglucose, and occurred despite significant hyperinsulinaemia in obese animals. Phosphorylation and inactivation of PDH complex in mouse heart muscle in starvation was attributed to a stable increase (2.7-fold) in the activity of PDH kinase as measured in extracts of mitochondria mediated by increased specific activity of a protein activator of PDH kinase (KAP) [Denyer, Kerbey & Randle (1986) Biochem. J. 239, 347-354]. In obese mice no such increase in kinase activity was observed, and we conclude that phosphorylation and inactivation of PDH complex in heart muscle in obesity is not mediated by KAP, but rather is a consequence of increased lipid oxidation.

SUBMITTER: Caterson ID

PROVIDER: S-EPMC1149289 | biostudies-other | 1988 Jul

REPOSITORIES: biostudies-other

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Pyruvate dehydrogenase-complex activity in brown adipose tissue of gold thioglucose-obese mice.

Project description:The activity of pyruvate dehydrogenase (PDH) complex and PDH kinase were measured in brown adipose tissue (BAT) of 4-week-gold thioglucose (GTG)-obese mice. The proportion of PDH complex in the active dephosphorylated form was 2-fold higher in BAT of post-absorptive obese mice compared with lean controls. This result was consistent with the higher circulating insulin concentration observed in GTG-obese mice. In both obese and lean mice the PDH-complex activity in BAT decreased after 24 h starvation and increased in response to supraphysiological insulin injection, indicating that the PDH complex is insulin-responsive in BAT of GTG-obese mice. There was no difference in the PDH kinase activity of BAT in post-absorptive or insulin-injected lean and obese mice, suggesting that the higher PDH-complex activity in obese mice was not due to decreased PDH kinase activity. There is no evidence for a decreased activity of PDH complex contributing to insulin resistance in BAT of 4-week-GTG-obese mice.

| S-EPMC1131707 | biostudies-other

Diurnal patterns of cardiac and hepatic pyruvate dehydrogenase complex activity in gold-thioglucose-obese mice.

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| S-EPMC1134621 | biostudies-other

Tissue differences in the response of the pyruvate dehydrogenase complex to a glucose load during the development of obesity in gold-thioglucose-obese mice.

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Metabolic and oncogenic adaptations to pyruvate dehydrogenase inactivation in fibroblasts.

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| S-EPMC6462518 | biostudies-literature

Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species.

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| S-EPMC9066178 | biostudies-literature

Role of individual phosphorylation sites in inactivation of pyruvate dehydrogenase complex in rat heart mitochondria.

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| S-EPMC1158198 | biostudies-other

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| S-EPMC9879793 | biostudies-literature

Pirin regulates pyruvate catabolism by interacting with the pyruvate dehydrogenase E1 subunit and modulating pyruvate dehydrogenase activity.

Project description:The protein pirin, which is involved in a variety of biological processes, is conserved from prokaryotic microorganisms, fungi, and plants to mammals. It acts as a transcriptional cofactor or an apoptosis-related protein in mammals and is involved in seed germination and seedling development in plants. In prokaryotes, while pirin is stress induced in cyanobacteria and may act as a quercetinase in Escherichia coli, the functions of pirin orthologs remain mostly uncharacterized. We show that the Serratia marcescens pirin (pirin(Sm)) gene encodes an ortholog of pirin protein. Protein pull-down and bacterial two-hybrid assays followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray ionization-tandem mass spectrometry analyses showed the pyruvate dehydrogenase (PDH) E1 subunit as a component interacting with the pirin(Sm) gene. Functional analyses showed that both PDH E1 subunit activity and PDH enzyme complex activity are inhibited by the pirin(Sm) gene in S. marcescens CH-1. The S. marcescens CH-1 pirin(Sm) gene was subsequently mutated by insertion-deletion homologous recombination. Accordingly, the PDH E1 and PDH enzyme complex activities and cellular ATP concentration increased up to 250%, 140%, and 220%, respectively, in the S. marcescens CH-1 pirin(Sm) mutant. Concomitantly, the cellular NADH/NAD(+) ratio increased in the pirin(Sm) mutant, indicating increased tricarboxylic acid (TCA) cycle activity. Our results show that the pirin(Sm) gene plays a regulatory role in the process of pyruvate catabolism to acetyl coenzyme A through interaction with the PDH E1 subunit and inhibiting PDH enzyme complex activity in S. marcescens CH-1, and they suggest that pirin(Sm) is an important protein involved in determining the direction of pyruvate metabolism towards either the TCA cycle or the fermentation pathways.

| S-EPMC1797226 | biostudies-literature

Expressing a cytosolic pyruvate dehydrogenase complex to increase free fatty acid production in Saccharomyces cerevisiae.

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| S-EPMC7730738 | biostudies-literature

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