scholarly journals Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway

Cell Reports ◽  
2020 ◽  
Vol 30 (5) ◽  
pp. 1417-1433.e7 ◽  
Author(s):  
Michael M. Dubreuil ◽  
David W. Morgens ◽  
Kanji Okumoto ◽  
Masanori Honsho ◽  
Kévin Contrepois ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pentose Phosphate Pathway ◽  
Pentose Phosphate ◽  
Systematic Identification

scholarly journals TIGAR regulates glycolysis in ischemic kidney proximal tubules

2015 ◽  
Vol 308 (4) ◽  
pp. F298-F308 ◽  
Author(s):  
Jinu Kim ◽  
Kishor Devalaraja-Narashimha ◽  
Babu J. Padanilam
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Pentose Phosphate Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pentose Phosphate ◽  
Atp Depletion ◽  
G6pd Activity ◽  
Histological Damage ◽  
Severe Ischemia

Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53-dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism.

scholarly journals The pentose phosphate pathway in Trypanosoma cruzi: a potential target for the chemotherapy of Chagas disease

2007 ◽  
Vol 79 (4) ◽  
pp. 649-663 ◽  
Author(s):  
Mariana Igoillo-Esteve ◽  
Dante Maugeri ◽  
Ana L. Stern ◽  
Paula Beluardi ◽  
Juan J. Cazzulo
Keyword(s):  
Oxidative Stress ◽  
Trypanosoma Cruzi ◽  
Pentose Phosphate Pathway ◽  
Single Copy ◽  
Pentose Phosphate ◽  
Site Directed Mutagenesis ◽  
Haploid Genome ◽  
Salt Bridges ◽  
Phosphogluconate Dehydrogenase ◽  
Genes Encoding

Trypanosoma cruzi is highly sensitive to oxidative stress caused by reactive oxygen species. Trypanothione, the parasite's major protection against oxidative stress, is kept reduced by trypanothione reductase, using NADPH; the major source of the reduced coenzyme seems to be the pentose phosphate pathway. Its seven enzymes are present in the four major stages in the parasite's biological cycle; we have cloned and expressed them in Escherichia coli as active proteins. Glucose 6-phosphate dehydrogenase, which controls glucose flux through the pathway by its response to the NADP/NADPH ratio, is encoded by a number of genes per haploid genome, and is induced up to 46-fold by hydrogen peroxide in metacyclic trypomastigotes. The genes encoding 6-phosphogluconolactonase, 6-phosphogluconate dehydrogenase, transaldolase and transketolase are present in the CL Brener clone as a single copy per haploid genome. 6-phosphogluconate dehydrogenase is very unstable, but was stabilized introducing two salt bridges by site-directed mutagenesis. Ribose-5-phosphate isomerase belongs to Type B; genes encoding Type A enzymes, present in mammals, are absent. Ribulose-5-phosphate epimerase is encoded by two genes. The enzymes of the pathway have a major cytosolic component, although several of them have a secondary glycosomal localization, and also minor localizations in other organelles.

scholarly journals Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart

2014 ◽  
Vol 306 (5) ◽  
pp. H709-H717 ◽  
Author(s):  
Claudio Vimercati ◽  
Khaled Qanud ◽  
Gianfranco Mitacchione ◽  
Danuta Sosnowska ◽  
Zoltan Ungvari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pentose Phosphate Pathway ◽  
Tissue Concentration ◽  
Glucose Consumption ◽  
Pentose Phosphate ◽  
Oxidative Pentose Phosphate Pathway ◽  
Stroke Work ◽  
Failing Heart

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼80 to ∼170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.

scholarly journals The Pentose Phosphate Pathway and Pyruvate Carboxylation after Neonatal Hypoxic-Ischemic Brain Injury

2014 ◽  
Vol 34 (4) ◽  
pp. 724-734 ◽  
Author(s):  
Eva MF Brekke ◽  
Tora S Morken ◽  
Marius Widerøe ◽  
Asta K Håberg ◽  
Ann-Mari Brubakk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Glucose Metabolism ◽  
Pentose Phosphate Pathway ◽  
De Novo ◽  
Pentose Phosphate ◽  
Adult Brain ◽  
Resonance Spectroscopy ◽  
Neonatal Brain ◽  
Artery Ligation ◽  
Pyruvate Carboxylation

The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-13C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using 1H- and 13C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress.

scholarly journals Methionine Metabolism Alters Oxidative Stress Resistanceviathe Pentose Phosphate Pathway

2016 ◽  
Vol 24 (10) ◽  
pp. 543-547 ◽  
Author(s):  
Kate Campbell ◽  
Jakob Vowinckel ◽  
Markus A. Keller ◽  
Markus Ralser
Keyword(s):  
Oxidative Stress ◽  
Pentose Phosphate Pathway ◽  
Pentose Phosphate ◽  
Methionine Metabolism

scholarly journals Pentose phosphate pathway activity parallels lipogenesis but not antioxidant processes in rat liver

2018 ◽  
Vol 314 (6) ◽  
pp. E543-E551 ◽  
Author(s):  
Eunsook S. Jin ◽  
Min Hee Lee ◽  
Rebecca E. Murphy ◽  
Craig R. Malloy
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Pentose Phosphate Pathway ◽  
Antioxidant Defense ◽  
Pentose Phosphate ◽  
Zucker Rats ◽  
Pathway Activity ◽  
Zucker Diabetic Fatty Rats ◽  
Obese Zucker Rats ◽  
Biomarkers Of Oxidative Stress

The pentose phosphate pathway (PPP) is widely assumed to play a key role in both reductive biosynthesis and protection from oxidative stress because it is the major source of NADPH. However, little is known about the activity of the PPP in fatty liver, which is characterized by both oxidative stress and lipogenesis. This study was designed to test whether the PPP is active in parallel with lipogenesis and antioxidant processes in the fatty liver of whole animals. Eight- and 16-wk-old obese Zucker diabetic fatty rats and their lean littermates received [U-13C3]glycerol, and 13C labeling patterns of glucose and triglycerides were analyzed for the assessment of hepatic PPP activity and the potentially related processes simultaneously. Oxidative stress, antioxidant activity, and NADPH-producing enzymes in the liver were further examined. Both PPP activity and lipogenesis increased in the fatty liver of young obese Zucker rats but decreased together in older obese Zucker rats. As expected, lipid peroxidation measured by malondialdehyde increased in the fatty liver of obese Zucker rats at both ages. However, evidence for antioxidant processes such as [glutathione] or activities of glutathione reductase, glutathione peroxidase, and catalase was not altered. Hepatic PPP activity paralleled lipogenesis but was dissociated from biomarkers of oxidative stress or antioxidant processes. In summary, NADPH from the PPP was presumably consumed for reductive biosynthesis rather than antioxidant defense in the fatty liver.

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