Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism

Chen, Tzu-Ling; Yang, Hung Chi; Hung, Cheng Yu; Ou, Meng Hsin; Pan, Yi Yun; Cheng, Mei; Stern, Arnold; Lo, Szecheng J.; Chiu, Daniel

doi:10.1038/cddis.2016.463

Cited by 32 publications

(49 citation statements)

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“…We noted that G6PD knockdown inhibited β-catenin expression, and cardiac edema occurred in the g6pd morphants of zebrafish. Moreover, G6PD knockdown can lead to the loss of asymmetric cell division in the embryos of C. elegans 12 and can prohibit macrophage differentiation (our unpublished data). These data indicate that the G6PD status affects cell differentiation and embryonic development, partly via the β-catenin pathway.…”

Section: Discussionmentioning

confidence: 80%

“…G6PD is a well-known housekeeping enzyme whose major function is to maintain cellular redox homeostasis 12 , 21 , 22 , and studies in knockout mouse reveals that G6PD plays a fundamental role in embryonic development. However, the detailed mechanism regarding why its knockout is embryonically lethal has not been clearly elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The study of a severe G6PD deficiency mouse model delineates that the initial development of all embryos, especially in early gestation, is unimpaired 9 . In Caenorhabditis elegans , G6PD deficiency has a strong impact on egg hatching and embryonic development; this is attributed to altered lipid metabolism 12 . All these data indicate that G6PD is vital in embryonic development and differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Lee

Shih

et al. 2018

Cell Death Dis

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Glucose-6-phosphate dehydrogenase (G6PD) is a housekeeping enzyme involved in the pentose phosphate shunt for producing nicotinamide adenine dinucleotide phosphate (NADPH). Severe G6PD deficiency leads to embryonic lethality, but the underlying mechanism is unclear. In the current study, the effects of G6PD on epithelial–mesenchymal transition (EMT), especially during embryonic development, were investigated. The knockdown of G6PD induced morphological changes, accompanied by the suppression of epithelial markers, E-cadherin and β-catenin, in A549 and MDCK cells. Such modulation of EMT was corroborated by the enhancement of migration ability in G6PD-knockdown A549 cells. Zebrafish embryos with g6pd knockdown exhibited downregulation of the E-cadherin/β-catenin adhesion molecules and impaired embryonic development through reduction in epiboly rate and increase in cell shedding at the embryo surface. The dysregulation in zebrafish embryonic development caused by g6pd knockdown could be rescued through human G6PD or CDH1 (E-cadherin gene) cRNA coinjection. The Smad3/miR-200b axis was dysregulated upon G6PD knockdown, and the reconstitution of SMAD3 in G6PD-knockdown A549 cells restored the expression of E-cadherin/β-catenin. The inhibition of NADPH oxidase (NOX) activation through the loss of p22phox signaling was involved in the dysregulation of the Smad3/miR-200b axis upon G6PD knockdown. The reconstitution of G6PD led to the recovery of the regulation of NOX/Smad3/miR-200b signaling and increased the expression of E-cadherin/β-catenin in G6PD-knockdown cells. Thus, these results suggest that in the EMT process, G6PD plays an important regulatory role as an integral component of the NOX/Smad3/miR-200b axis.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Lee

Shih

et al. 2018

Cell Death Dis

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“…Aberrations in glycerolipid biosynthesis have been associated with G6PD − from nematodes to humans ( 51 ). Increased activity of phospholipase A2 is observed during eryptosis which is enhanced in G6PD − subjects ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Redox Status, Procoagulant Activity, and Metabolome of Fresh Frozen Plasma in Glucose 6-Phosphate Dehydrogenase Deficiency

et al. 2018

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ObjectiveTransfusion of fresh frozen plasma (FFP) helps in maintaining the coagulation parameters in patients with acquired multiple coagulation factor deficiencies and severe bleeding. However, along with coagulation factors and procoagulant extracellular vesicles (EVs), numerous bioactive and probably donor-related factors (metabolites, oxidized components, etc.) are also carried to the recipient. The X-linked glucose 6-phosphate dehydrogenase deficiency (G6PD−), the most common human enzyme genetic defect, mainly affects males. By undermining the redox metabolism, the G6PD− cells are susceptible to the deleterious effects of oxidants. Considering the preferential transfusion of FFP from male donors, this study aimed at the assessment of FFP units derived from G6PD− males compared with control, to show whether they are comparable at physiological, metabolic and redox homeostasis levels.MethodsThe quality of n = 12 G6PD− and control FFP units was tested after 12 months of storage, by using hemolysis, redox, and procoagulant activity-targeted biochemical assays, flow cytometry for EV enumeration and phenotyping, untargeted metabolomics, in addition to statistical and bioinformatics tools.ResultsHigher procoagulant activity, phosphatidylserine positive EVs, RBC-vesiculation, and antioxidant capacity but lower oxidative modifications in lipids and proteins were detected in G6PD− FFP compared with controls. The FFP EVs varied in number, cell origin, and lipid/protein composition. Pathway analysis highlighted the riboflavin, purine, and glycerolipid/glycerophospholipid metabolisms as the most altered pathways with high impact in G6PD−. Multivariate and univariate analysis of FFP metabolomes showed excess of diacylglycerols, glycerophosphoinositol, aconitate, and ornithine but a deficiency in riboflavin, flavin mononucleotide, adenine, and arginine, among others, levels in G6PD− FFPs compared with control.ConclusionOur results point toward a different redox, lipid metabolism, and EV profile in the G6PD− FFP units. Certain FFP-needed patients may be at greatest benefit of receiving FFP intrinsically endowed by both procoagulant and antioxidant activities. However, the clinical outcome of G6PD− FFP transfusion would likely be affected by various other factors, including the signaling potential of the differentially expressed metabolites and EVs, the degree of G6PD−, the redox status in the recipient, the amount of FFP units transfused, and probably, the storage interval of the FFP, which deserve further investigation by future studies.

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“…Novel functions of G6PD in cellular physiology have been discovered over recent years [3]. G6PD is required for life as severe deficiency of G6PD in mammals and nematodes is lethal for survival and reproduction [4, 5] and plays an important role in embryogenesis [6, 7].…”

Section: Introductionmentioning

confidence: 99%

IDH-1 deficiency induces growth defects and metabolic alterations in GSPD-1-deficient Caenorhabditis elegans

Yang

Liu

et al. 2019

J Mol Med

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NADPH is a reducing equivalent that maintains redox homeostasis and supports reductive biosynthesis. Lack of major NADPH-producing enzymes predisposes cells to growth retardation and demise. It was hypothesized that double deficiency of the NADPH-generating enzymes, GSPD-1 (Glucose-6-phosphate 1-dehydrogenase), a functional homolog of human glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, and IDH-1 (isocitrate dehydrogenase-1) affect growth and development in the nematode, Caenorhabditis elegans ( C. elegans ). The idh-1 ; gspd-1 ( RNAi ) double-deficient C. elegans model displayed shrinkage of body size, growth retardation, slowed locomotion, and impaired molting. Global metabolomic analysis was employed to address whether or not metabolic pathways were altered by severe NADPH insufficiency by the idh-1 ; gspd-1 ( RNAi ) double-deficiency. The principal component analysis (PCA) points to a distinct metabolomic profile of idh-1 ; gspd-1 ( RNAi ) double-deficiency. Further metabolomic analysis revealed that NADPH-dependent and glutamate-dependent amino acid biosynthesis were significantly affected. The reduced pool of amino acids may affect protein synthesis, as indicated by the absence of NAS-37 expression during the molting process. In short, double deficiency of GSPD-1 and IDH-1 causes growth retardation and molting defects, which are, in part, attributed to defective protein synthesis, possibly mediated by altered amino acid biosynthesis and metabolism in C. elegans . Electronic supplementary material The online version of this article (10.1007/s00109-018-01740-2) contains supplementary material, which is available to authorized users.

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Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism

Cited by 32 publications

References 58 publications

Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis

Redox Status, Procoagulant Activity, and Metabolome of Fresh Frozen Plasma in Glucose 6-Phosphate Dehydrogenase Deficiency

IDH-1 deficiency induces growth defects and metabolic alterations in GSPD-1-deficient Caenorhabditis elegans

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