Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis

Darghouth, Dhouha; Koehl, Bérengère; Heilier, Jean-François; Madalinski, Geoffrey; Bovee, Petra; Bosman, Giel; Delaunay, Jean; Junot, Christophe; Roméo, Paul-Henri

doi:10.3324/haematol.2011.045179

Cited by 33 publications

(35 citation statements)

References 18 publications

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“…Oxidative damage to erythrocytes has been widely studied to explain destructive events in numerous hematological disorders [37,38]. In the present study, we observed a significant decrease in glucose metabolism enzyme activity of rat RBCs after 6 weeks storage.…”

Section: Discussionsupporting

confidence: 66%

Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Xiong

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although red blood cells (RBCs) transfusions can be lifesaving, they are not without risk. RBCs storage is associated with the abnormal metabolism of glutathione (GSH), which may increase the risk of the oxidative damage of RBCs after transfusion. The responsible mechanisms remain unknown. Methods: We determined the L-cysteine efflux and influx by evaluating the changes of free -SH concentrations in stored RBCs. The glutamate cysteine ligase (GCL) activities and protein content in stored RBCs was determined by fluorescence assay and western blotting. In addition, the glucose metabolism enzyme activity of RBCs was measured by spectrophotometric assay under in vitro incubation conditions. Results: We found that both L-cysteine transport and GCL activity significantly declined, thereby inducing the dysfunction of GSH synthesis during blood storage, which could be attenuated by ATP supplement and DTT treatment. In addition, the glycometabolic enzyme (G6PDH, HK, PK and LDH) activity significantly decreased after 6 weeks storage. Oxidant stress-induced dysfunction in glucose metabolism was the driving force for decreased GSH synthesis during storage. Conclusion: These experimental findings reflect an underlying molecular mechanism that oxidant stress induced glucose metabolism dysfunction contribute to decreased GSH synthesis in stored RBCs.

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Section: Discussionsupporting

confidence: 66%

Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Xiong

Wang

et al. 2018

Cell Physiol Biochem

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“…Oxidative injury to erythrocytes has been widely studied and found to contribute to the destructive events observed in many hematological disorders [45][46][47][48]. In the present study, we observed a significant decrease in glucose metabolism enzyme activity of rat RBCs after exhaustive exercise.…”

Section: Discussionsupporting

confidence: 68%

Inhibition of Glutathione Synthesis Induced by Exhaustive Running Exercise via the Decreased Influx Rate of L-Cysteine in Rat Erythrocytes

Xiong

Zhou²,

Yu³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The main purpose of this study was to investigate the effect of exhaustive exercise on L-cysteine uptake and its effect on erythrocyte glutathione (GSH) synthesis and metabolism. Methods: Rats were divided into three groups: sedentary control (C), exhaustive running exercise (ERE) and moderate running exercise (MRE) (n=12 rats/group). We determined the L-cysteine efflux and influx in vitro in rat erythrocytes and its relationship with GSH synthesis. Total anti-oxidant potential of plasma was measured in terms of the ferric reducing ability of plasma (FRAP) values for each exercise group. In addition, the glucose metabolism enzyme activity of erythrocytes was also measured under in vitro incubation conditions. Results: Biochemical studies confirmed that exhaustive running exercise significantly increased oxidative damage parameters in thiobarbituric acid reactive substances (TBARS) and methemoglobin levels. Pearson correlation analysis suggested that L-cysteine influx was positively correlated with erythrocyte GSH synthesis and FRAP values in both the control and exercise groups. In vitro oxidation incubation significantly decreased the level of glucose metabolism enzyme activity in the control group. Conclusion: We presented evidence of the exhaustive exercise-induced inhibition of GSH synthesis due to a dysfunction in L-cysteine transport. In addition, oxidative stress-induced changes in glucose metabolism were the driving force underlying decreased L-cysteine uptake in the exhaustive exercise group.

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“…The mutated variants might titrate or liberate a component of the complex associated to the membrane or to the cytoskeleton which could then play a secondary role on the activation of cation transport pathways responsible for the stomatocytosis cation leak. Metabolomics studies were recently performed on red cells of 4 patients expressing the HsRhAG F65S variant [39]. A raise in the concentrations of glycolysis end-products, such as pyruvate or lactate, were found as a metabolic signature of OHSt patients' erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

SNPs Altering Ammonium Transport Activity of Human Rhesus Factors Characterized by a Yeast-Based Functional Assay

et al. 2013

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Proteins of the conserved Mep-Amt-Rh family, including mammalian Rhesus factors, mediate transmembrane ammonium transport. Ammonium is an important nitrogen source for the biosynthesis of amino acids but is also a metabolic waste product. Its disposal in urine plays a critical role in the regulation of the acid/base homeostasis, especially with an acid diet, a trait of Western countries. Ammonium accumulation above a certain concentration is however pathologic, the cytotoxicity causing fatal cerebral paralysis in acute cases. Alteration in ammonium transport via human Rh proteins could have clinical outcomes. We used a yeast-based expression assay to characterize human Rh variants resulting from non synonymous single nucleotide polymorphisms (nsSNPs) with known or unknown clinical phenotypes and assessed their ammonium transport efficiency, protein level, localization and potential trans-dominant impact. The HsRhAG variants (I61R, F65S) associated to overhydrated hereditary stomatocytosis (OHSt), a disease affecting erythrocytes, proved affected in intrinsic bidirectional ammonium transport. Moreover, this study reveals that the R202C variant of HsRhCG, the orthologue of mouse MmRhcg required for optimal urinary ammonium excretion and blood pH control, shows an impaired inherent ammonium transport activity. Urinary ammonium excretion was RHcg gene-dose dependent in mouse, highlighting MmRhcg as a limiting factor. HsRhCGR202C may confer susceptibility to disorders leading to metabolic acidosis for instance. Finally, the analogous R211C mutation in the yeast ScMep2 homologue also impaired intrinsic activity consistent with a conserved functional role of the preserved arginine residue. The yeast expression assay used here constitutes an inexpensive, fast and easy tool to screen nsSNPs reported by high throughput sequencing or individual cases for functional alterations in Rh factors revealing potential causal variants.

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Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis

Abstract: ABSTRACTmetabolites from purified human RBCs. 8 Here we use this strategy to distinguish metabolic changes in RBCs from OHSt patients in order to fully characterize the metabolic bases of this disease.

Cited by 33 publications

References 18 publications

Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Inhibition of Glutathione Synthesis Induced by Exhaustive Running Exercise via the Decreased Influx Rate of L-Cysteine in Rat Erythrocytes

SNPs Altering Ammonium Transport Activity of Human Rhesus Factors Characterized by a Yeast-Based Functional Assay

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