Pyruvate dehydrogenase kinase

About: Pyruvate dehydrogenase kinase is a research topic. Over the lifetime, 4224 publications have been published within this topic receiving 161052 citations. The topic is also known as: [pyruvate dehydrogenase (lipoamide)] kinase & pyruvate dehydrogenase (lipoamide) kinase.

Hyperpolarized 13C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Abstract: Proinflammatory mononuclear phagocytes (MPs) play a crucial role in the progression of multiple sclerosis (MS) and other neurodegenerative diseases. Despite advances in neuroimaging, there are currently limited available methods enabling noninvasive detection of MPs in vivo. Interestingly, upon activation and subsequent differentiation toward a proinflammatory phenotype MPs undergo metabolic reprogramming that results in increased glycolysis and production of lactate. Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) is a clinically translatable imaging method that allows noninvasive monitoring of metabolic pathways in real time. This method has proven highly useful to monitor the Warburg effect in cancer, through MR detection of increased HP [1-13C]pyruvate-to-lactate conversion. However, to date, this method has never been applied to the study of neuroinflammation. Here, we questioned the potential of 13C MRSI of HP [1-13C]pyruvate to monitor the presence of neuroinflammatory lesions in vivo in the cuprizone mouse model of MS. First, we demonstrated that 13C MRSI could detect a significant increase in HP [1-13C]pyruvate-to-lactate conversion, which was associated with a high density of proinflammatory MPs. We further demonstrated that the increase in HP [1-13C]lactate was likely mediated by pyruvate dehydrogenase kinase 1 up-regulation in activated MPs, resulting in regional pyruvate dehydrogenase inhibition. Altogether, our results demonstrate a potential for 13C MRSI of HP [1-13C]pyruvate as a neuroimaging method for assessment of inflammatory lesions. This approach could prove useful not only in MS but also in other neurological diseases presenting inflammatory components.

Regulation in vitro and in vivo of adenosine 3':5'-monophosphate-dependent inactivation of rat-liver pyruvate kinase type L.

Abstract: The cyclic-AMP-dependent inactivation of pyruvate kinase L has been studied in a crude Sephadex filtrate of isolated hepatocytes. This inactivation requires the presence of Mg-ATP (apparent Km= 0.1 mM) and a half-maximal rate of inactivation was obtained in the presence of 0.15 μM cyclic AMP. It was inhibited by physiological concentrations of phosphoenolpyruvate and by micromolar concentrations of fructose bisphosphate and these inhibitory effects were counteracted by Mg-ATP and by several l-form amino acids such as cysteine, alanine, serine, phenylalanine, which are also ligands of pyruvate kinase. As a rule, it appears that effectors that increase the activity of the enzyme are also those which prevent its cyclic-AMP-dependent inactivation and vice-versa. Considering the potentially important role of phosphoenolpyruvate concentration in the control of gluconeogenesis, experiments were performed to check if the inhibitory action of this metabolite on the inactivation of pyruvate kinase was of importance in vivo. We found that the concentration of phosphoenolpyruvate was higher than normal in the livers of anesthetized rats in conditions like fasting and diabetes in which the rate of gluconeogenesis is known to be higher and the activity of pyruvate kinase lower than normally. The reverse was true upon sucrose feeding. Inactivation of pyruvate kinase was induced in vivo by the administration of glucagon. This inactivation was less important in the livers with high concentrations of phosphoenolpyruvate and vice-versa. It is proposed that phosphoenolpyruvate exerts an important buffering effect in the variations of the rate of gluconeogenesis.

The Clinical and Biochemical Spectrum of Human Pyruvate Dehydrogenase Complex Deficiency

Abstract: Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidosis in infants and young children.' In almost all cases, the basic defect appears to be in the El component of PDC and, in particular, in the Ela subunit.24 In spite of numerous reports of PDC deficiency in humans, there is still significant controversy concerning the incidence and the clinical and biochemical spectrum of this ~ondi t ion .~ Some of the confusion regarding PDC deficiency in humans has arisen because of difficulties in establishing the diagnosis by assay of the enzyme complex in readily available samples from patients. However, the development of more reliable assays,' the availability of immunochemical methods for analysis of structural changes in specific components of the and the isolation of recombinant DNA probes for studies of the underlying genetic defects8-\" have greatly improved the accuracy of diagnosis. The heterogeneity of PDC deficiency can be assessed from recently reported cases with confidence that the patients described do indeed have a primary genetic defect in the PDC. The following discussion will be limited to patients with defects in the E l a component of PDC. From our own experience and from recently reported cases, it is apparent that this form of PDC deficiency in humans is an extremely heterogeneous condition. The characteristic features of the disorder are metabolic acidosis and neurological dysfunction. In contrast with many other inborn errors of metabolism which affect cerebral function, PDC deficiency is distinguished by the presence of significant structural abnormalities in the central nervous system (CNS). Within this general clinical presentation, however, there is a wide range in the severity of symptoms and the clinical course of the condition. In the most severe form of PDC deficiency, lactic acidosis develops within hours of birth and the blood lactate concentration rapidly attains levels as high as 10-20 mM.4 The lactic acidosis is almost always refractory to all attempts a t specific therapy, and most of these patients die in the newborn period. Patients with less severe forms of PDC deficiency generally present later, and their clinical course is characterized by episodes of severe lactic acidosis, often precipitated by intercurrent illness.\" Blood pyruvate and

Use of toluene-permeabilized mitochondria to study the regulation of adipose tissue pyruvate dehydrogenase in situ: further evidence that insulin acts through stimulation of pyruvate dehydrogenase phosphate phosphatase

Abstract: Rat epididymal-adipose-tissue mitochondria were made selectively permeable to small molecules without the loss of matrix enzymes by treating the mitochondria with toluene under controlled conditions. With this preparation the entire pyruvate dehydrogenase system was shown to be retained within the mitochondrial matrix and to retain its normal catalytic activity. By using dilute suspensions of these permeabilized mitochondria maintained in the cuvette of a spectrophotometer, it was possible to monitor changes of pyruvate dehydrogenase activity continuously while the activities of the interconverting kinase and phosphatase could be independently manipulated. Permeabilized mitochondria were prepared from control and insulin-treated adipose tissue, and the properties of both the pyruvate dehydrogenase kinase and the phosphatase were compared in situ. No difference in kinase activity was detected, but increases in phosphatase activity were observed in permeabilized mitochondria from insulin-treated tissue. Further studies showed that the main effect of insulin treatment was a decrease in the apparent Ka of the phosphatase for Mg2+, in agreement with earlier studies with mitochondria made permeable to Mg2+ by using the ionophore A23187 [Thomas, Diggle & Denton (1986) Biochem. J. 238, 83-91]. No effects of spermine were detected, although spermine diminishes the Ka of purified phosphatase preparations for Mg2+. Since effects of insulin on pyruvate dehydrogenase phosphatase activity are not evident in mitochondrial extracts, it is concluded that insulin may act by altering some high-Mr component which interacts with the pyruvate dehydrogenase system within intact or permeabilized mitochondria, but not when the mitochondrial membranes are disrupted.