Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Wetering, Cheryl van de; Manuel, Allison M.; Sharafi, Mona; Aboushousha, Reem; Qian, Xi; Erickson, Cuixia; MacPherson, Maximilian B.; Chan, Garrett J.; Adcock, Ian M.; Zounemat-Kermani, Nazanin; Schleich, Florence; Louis, Renaud; Bohrnsen, Eric; D’Alessandro, Angelo; Wouters, Emiel F.M.; Reynaert, Niki L.; Li, Jianing; Wolf, Charles; Henderson, Colin J.; Lundblad, Lennart K. A.; Poynter, Matthew E.; Dixon, Anne E.; Irvin, Charles G.; Vliet, Albert van der; Velden, Jos van der; Janssen–Heininger, Yvonne M. W.

doi:10.1016/j.redox.2021.102160

Cited by 25 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The copyright holder for this preprint this version posted February 14, 2023. ; https://doi.org/10.1101/2023.02.13.528368 doi: bioRxiv preprint Interestingly, we found that the SS genotype is associated with a metabolic blockade at a critical ATP-generating step of late glycolysis, which is catalyzed by redox sensitive PK. 72 ATP is a key energy token to fuel RBC homeostatic processes, including degradation of oxidized components via ATP-dependent ubiquitinylation and proteasomal activity in SCD RBCs. 73 PK oxidation state has been implicated in the etiology of asthma through regulation of pro-inflammatory cytokines (e.g., interleukin 1β) 74 and dysregulated PK isoform splicing and activity is a hallmark of pulmonary hypertension, 75,76 a common comorbidity in SCD.…”

Section: Discussionmentioning

confidence: 99%

In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

D’Alessandro

Nouraie

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs) in vivo. The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events, and HbF related to hydroxyurea therapy. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and hydroxyurea and transfusion therapy on sickle RBC metabolism. Data were collated in an online portal and show that the Hb SS genotype is associated with significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1-phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP-generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox-sensitive pyruvate kinase. Increasing in vivo concentrations of HbA improved glycolytic flux and normalized the HbS erythrocyte metabolome. An unexpectedly limited metabolic effect of hydroxyurea and HbF was observed, possibly related to the modest induction of HbF in this cohort. The metabolic signature of HbS RBCs correlated with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

D’Alessandro

Nouraie

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…This is an unexpected finding since we would have predicted that radiation-induced decreases in energy metabolism (here observed in multiple organs at the glycolytic and mitochondrial level) would have corresponded to increased breakdown of high-energy phosphate purines (ATP and AMPwhich we indeed observed) and increases in oxidant stress. Declines in glycolysis were noted upstream to pyruvate kinase, suggesting an effect of irradiation and iron levels (perhaps through Fenton chemistry) on redox-sensitive reactive thiols in the rate-limiting steps of glycolysis (especially glyceraldehyde 3-phosphate dehydrogenase 39 and pyruvate kinase 40 ). With respect to oxidant stress, the main signature identified hereas a function of radiation dose and exacerbated by iron infusionwas the activation of the pentose phosphate pathway, the decline in glutathione pools and oxidation of methionine and taurine in plasma and RBCs.…”

Section: ■ Discussionmentioning

confidence: 99%

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs

et al. 2022

View full text Add to dashboard Cite

Investigating the metabolic effects of radiation is critical to understand the impact of radiotherapy, space travel, and exposure to environmental radiation. In patients undergoing hemopoietic stem cell transplantation, iron overload is a common risk factor for poor outcomes. However, no studies have interrogated the multiorgan effects of these treatments concurrently. Herein, we use a model that recapitulates transfusional iron overload, a condition often observed in chronically transfused patients. We applied an omics approach to investigate the impact of both the iron load and irradiation on the host metabolome. The results revealed dose-dependent effects of irradiation in the red blood cells, plasma, spleen, and liver energy and redox metabolism. Increases in polyamines and purine salvage metabolites were observed in organs with high oxygen consumption including the heart, kidneys, and brain. Irradiation also impacted the metabolism of the duodenum, colon, and stool, suggesting a potential effect on the microbiome. Iron infusion affected the response to radiation in the organs and blood, especially in erythrocyte polyamines and spleen antioxidant metabolism, and affected glucose, methionine, and glutathione systems and tryptophan metabolism in the liver, stool, and the brain. Together, the results suggest that radiation impacts metabolism on a multiorgan level with a significant interaction of the host iron status.

show abstract

“…Knockdown or inhibition of PKM2 expression using short hairpin RNA (shRNA) or shikonin can significantly reduce the release of HMGB1 in activated macrophages ( 11 ). In addition, stimulation of colon cancer cells using LPS led to increased production of TNF-α and IL-1β in a PKM2/STAT3-dependent manner ( 12 , 13 ). LPS can induce nuclear translocation of PKM2 and bind to the STAT3 promoter to activate and enhance transcription.…”

Section: Pkm2 Participates In the Innate Immune Responsementioning

confidence: 99%

Research progress on the role of PKM2 in the immune response

Liu

2022

Front. Immunol.

View full text Add to dashboard Cite

Pyruvate kinase (PK) is a key enzyme that catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate, and is responsible for the production of ATP during glycolysis. As another important isozyme of PK, pyruvate kinase M2 (PKM2) exists in cells with high levels of nucleic acid synthesis, such as normal proliferating cells (e.g., lymphocytes and intestinal epithelial cells), embryonic cells, adult stem cells, and tumor cells. With further research, PKM2, as an important regulator of cellular pathophysiological activity, has attracted increasing attention in the process of autoimmune response and inflammatory. In this re]view, we examine the contribution of PKM2 to the human immune response. Further studies on the immune mechanisms of PKM2 are expected to provide more new ideas and drug targets for immunotherapy of inflammatory and autoimmune diseases, guiding drug development and disease treatment.

show abstract

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Cited by 25 publications

References 50 publications

In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs

Research progress on the role of PKM2 in the immune response

Contact Info

Product

Resources

About