scholarly journals The Drosophila mitochondrial citrate carrier regulates L-2-hydroxyglutarate accumulation by coupling the tricarboxylic acid cycle with glycolysis

2018 ◽  
Author(s):  
Hongde Li ◽  
Alexander J. Hurlburt ◽  
Jason M. Tennessen
Keyword(s):  
Gene Expression ◽  
Tricarboxylic Acid Cycle ◽  
Lactate Production ◽  
Cellular Metabolism ◽  
Tricarboxylic Acid ◽  
Acid Cycle ◽  
Glucose Catabolism ◽  
Elevated Glucose ◽  
Citrate Carrier ◽  
Citrate Efflux

AbstractThe oncometabolites D- and L-2-hydroxyglutarate (2HG) broadly interfere with cellular metabolism, physiology, and gene expression. A key regulator of 2HG metabolism is the mitochondrial citrate carrier (CIC), which, when mutated, promotes excess D-/L-2HG accumulation. The mechanism by which CIC influences 2HG levels, however, remains unknown. Here we studied the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, to explore the mechanisms linking mitochondrial citrate efflux to L-2HG metabolism. Our findings demonstrate that decreased Drosophila CIC activity results in elevated glucose catabolism and increased lactate production, thereby creating a metabolic environment that inhibits L-2HG degradation.

scholarly journals Human Prostate Cancer Is Characterized by an Increase in Urea Cycle Metabolites

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1814 ◽  
Author(s):  
Andras Franko ◽  
Yaping Shao ◽  
Martin Heni ◽  
Jörg Hennenlotter ◽  
Miriam Hoene ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Urea Cycle ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Human Prostate Cancer ◽  
Acid Cycle ◽  
Lower Survival Rate ◽  
Nfκb Pathway ◽  
Cancer Tissues

Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.

scholarly journals Endogenous 2-oxoacids differentially regulate expression of oxygen sensors

2004 ◽  
Vol 380 (2) ◽  
pp. 419-424 ◽  
Author(s):  
Clifton Lee DALGARD ◽  
Huasheng LU ◽  
Ahmed MOHYELDIN ◽  
Ajay VERMA
Keyword(s):  
Gene Expression ◽  
Nuclear Translocation ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Oxygen Sensors ◽  
Dependent Manner ◽  
Acid Cycle ◽  
Disease States ◽  
The Stability ◽  
Regulated Gene Expression

Adaptations to change in oxygen availability are crucial for survival of multi-cellular organisms and are also implicated in several disease states. Such adaptations rely upon gene expression regulated by the heterodimeric transcription factors HIFs (hypoxia-inducible factors). Enzymes that link changes in oxygen tensions with the stability and transcriptional activity of HIFs are considered as oxygen sensors. These enzymes are oxygen-, iron- and 2-oxoglutarate-dependent dioxygenases that hydroxylate key proline and asparagine residues in HIFα subunits. The constitutive inhibitory action of these enzymes on HIFs is relieved by hypoxia and by agents that displace iron or 2-oxoglutarate. Two of the enzymes, HPH (HIF prolyl hydroxylase)-1 and HPH-2, are known to be inducible by hypoxia in a HIF-dependent manner. This suggests the existence of a novel feedback loop for adjusting hypoxia-regulated gene expression. We have recently shown that HIF-1α stability, HIF-1 nuclear translocation and HIF-mediated gene expression in human glioma cell lines can be stimulated by pyruvate independently of hypoxia. In the present study we show that the endogenous 2-oxoacid oxaloacetate can also activate HIF-mediated gene expression. Pyruvate and oxaloacetate treatment of cells also up-regulates HPH-1 and HPH-2, but not HPH-3 or the HIF asparaginyl hydroxylase FIH-1 (factor inhibiting HIF). Regulation of HIF-1 and the expression of HPH homologue genes can thus be influenced by specific glycolytic and tricarboxylic acid cycle metabolites. These findings may underlie important interactions between oxygen homoeostasis, glycolysis, the tricarboxylic acid cycle and gluconeogenesis.

scholarly journals Anaerobic rat heart. Effects of glucose and tricarboxylic acid-cycle metabolites on metabolism and physiological performance

1970 ◽  
Vol 118 (2) ◽  
pp. 221-227 ◽  
Author(s):  
D. G. Penney ◽  
J. Cascarano
Keyword(s):  
Energy Expenditure ◽  
Rat Heart ◽  
Cell Function ◽  
Tricarboxylic Acid Cycle ◽  
Systolic Pressure ◽  
Lactate Production ◽  
Tricarboxylic Acid ◽  
Acid Cycle ◽  
Physiological Performance ◽  
Production Ratio

1. The ability of tricarboxylic acid-cycle metabolites to influence the physiological performance of the perfused anaerobic rat heart was investigated. Energy expenditure/h [(beats/min)×60×systolic pressure/g of protein] for various anoxic conditions compared with oxygenated control hearts were: 5mm-glucose, 4.5%; 20mm- or 40mm-glucose, 10%; 20mm-glucose plus fumerate+malate+glutamate, 29%; 20mm-glucose plus oxaloacetate and α-oxoglutarate, 31%. 2. The energy expenditure/lactate production ratio was increased by the tricarboxylic acid-cycle metabolites, indicating that alterations in anaerobic physiological performance did not result from changes in glycolysis. 3. Analysis of tissue constituents provided further indication of an enhanced energy status for fumarate+malate+glutamate- and oxaloacetate+α-oxoglutarate-perfused hearts; tissue concentrations of both glycogen and ATP were higher than in the 20mm-glucose-perfused groups. 4. A marked increase in the accumulation of succinate in tissues perfused with oxaloacetate+α-oxoglutarate or fumarate+malate+glutamate provided further evidence that these metabolites were stimulating mitochondrial energy production under anoxia. 5. These studies indicate that mitochondrial ATP production can be stimulated in an isolated mammalian tissue perfused under anaerobiosis with a resulting enhancement of cell function.

scholarly journals Neisseria meningitidis Uses Sibling Small Regulatory RNAs To Switch from Cataplerotic to Anaplerotic Metabolism

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Yvonne Pannekoek ◽  
Robert A. G. Huis in ‘t Veld ◽  
Kim Schipper ◽  
Sandra Bovenkerk ◽  
Gertjan Kramer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neisseria Meningitidis ◽  
Tricarboxylic Acid Cycle ◽  
Regulation Of Gene Expression ◽  
Stringent Response ◽  
Tricarboxylic Acid ◽  
Metabolic Adaptation ◽  
Acid Cycle ◽  
Small Regulatory Rnas ◽  
Regulatory Rnas

ABSTRACT Neisseria meningitidis (the meningococcus) is primarily a commensal of the human oropharynx that sporadically causes septicemia and meningitis. Meningococci adapt to diverse local host conditions differing in nutrient supply, like the nasopharynx, blood, and cerebrospinal fluid, by changing metabolism and protein repertoire. However, regulatory transcription factors and two-component systems in meningococci involved in adaptation to local nutrient variations are limited. We identified novel sibling small regulatory RNAs ( Neisseria metabolic switch regulators [NmsRs]) regulating switches between cataplerotic and anaplerotic metabolism in this pathogen. Overexpression of NmsRs was tolerated in blood but not in cerebrospinal fluid. Expression of six tricarboxylic acid cycle enzymes was downregulated by direct action of NmsRs. Expression of the NmsRs themselves was under the control of the stringent response through the action of RelA. Small sibling regulatory RNAs of meningococci, controlling general metabolic switches, add an exciting twist to their versatile repertoire in bacterial pathogens. IMPORTANCE Regulatory small RNAs (sRNAs) of pathogens are coming to be recognized as highly important components of riboregulatory networks, involved in the control of essential cellular processes. They play a prominent role in adaptation to physiological changes as represented by different host environments. They can function as posttranscriptional regulators of gene expression to orchestrate metabolic adaptation to nutrient stresses. Here, we identified highly conserved sibling sRNAs in Neisseria meningitidis which are functionally involved in the regulation of gene expression of components of the tricarboxylic acid cycle. These novel sibling sRNAs that function by antisense mechanisms extend the so-called stringent response which connects metabolic status to colonization and possibly virulence as well as pathogenesis in meningococci. IMPORTANCE Regulatory small RNAs (sRNAs) of pathogens are coming to be recognized as highly important components of riboregulatory networks, involved in the control of essential cellular processes. They play a prominent role in adaptation to physiological changes as represented by different host environments. They can function as posttranscriptional regulators of gene expression to orchestrate metabolic adaptation to nutrient stresses. Here, we identified highly conserved sibling sRNAs in Neisseria meningitidis which are functionally involved in the regulation of gene expression of components of the tricarboxylic acid cycle. These novel sibling sRNAs that function by antisense mechanisms extend the so-called stringent response which connects metabolic status to colonization and possibly virulence as well as pathogenesis in meningococci.

scholarly journals Die Wirkung von 6-Furfurylaminopurin auf die Atmung von Zellsüspensionen von Nicotiana tabacum

1963 ◽  
Vol 18 (11) ◽  
pp. 942-946 ◽  
Author(s):  
L. Bergmann
Keyword(s):  
Oxygen Consumption ◽  
Nicotiana Tabacum ◽  
Glucose Uptake ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Cell Suspensions ◽  
Tissue Cultures ◽  
Acid Cycle ◽  
Glucose Catabolism

6-Furfurylaminopurine (“kinetin”) has been found to reduce markedly the respiration of cell suspensions from tissue cultures of Nicotiana tabacum var. “Samsun” in glucose containing media. The observed reduction in the oxygen consumption is not caused by an inhibition of the glucose uptake by the cells. Pyruvate, succinate, and α-ketoglutarate can restore the respiration of cells inhibited by kinetin. The increased oxygen consumption following the addition of the acids is accompanied by an increased R.Q. It is concluded therefore, that kinetin does not inhibit the tricarboxylic acid cycle, and the suggestion is put forward that kinetin acts via the Embden- Meyerhof - pathway of the glucose catabolism.

Analysis of glucose metabolism in diabetic rat retinas

2006 ◽  
Vol 290 (6) ◽  
pp. E1057-E1067 ◽  
Author(s):  
M. Shamsul Ola ◽  
Deborah A. Berkich ◽  
Yuping Xu ◽  
M. Todd King ◽  
Thomas W. Gardner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Glucose Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Lactate Production ◽  
Tricarboxylic Acid ◽  
Diabetic Rats ◽  
Glycolytic Flux ◽  
Acid Cycle

This study was conceived in an effort to understand cause and effect relationships between hyperglycemia and diabetic retinopathy. Numerous studies show that hyperglycemia leads to oxidative stress in the diabetic retinas, but the mechanisms that generate oxidative stress have not been resolved. Increased electron pressure on the mitochondrial electron transfer chain, increased generation of cytosolic NADH, and decreases in cellular NADPH have all been cited as possible sources of reactive oxygen species and nitrous oxide. In the present study, excised retinas from control and diabetic rats were exposed to euglycemic and hyperglycemic conditions. Using a microwave irradiation quenching technique to study retinas of diabetic rats in vivo, glucose, glucose-derived metabolites, and NADH oxidation/reduction status were measured. Studying excised retinas in vitro, glycolytic flux, lactate production, and tricarboxylic acid cycle flux were evaluated. Enzymatically assayed glucose 6-phosphate and fructose 6-phosphate were only slightly elevated by hyperglycemia and/or diabetes, but polyols were increased dramatically. Cytosolic NADH-to-NAD ratios were not elevated by hyperglycemia nor by diabetes in vivo or in vitro. Tricarboxylic acid cycle flux was not increased by the diabetic state nor by hyperglycemia. On the other hand, small increases in glycolytic flux were observed with hyperglycemia, but glycolytic flux was always lower in diabetic compared with control animals. An observed decrease in activity of glyceraldehyde-3-phosphate dehydrogenase may be partially responsible for slow glycolytic flux for retinas of diabetic rats. Therefore, it is concluded that glucose metabolism, downstream of hexokinase, is not elevated by hyperglycemia or diabetes. Metabolites upstream of glucose such as the sorbitol pathway (which decreases NADPH) and polyol synthesis are increased.

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