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Biography

Dr. DTY Chiu completed his PhD in Biochemistry at the University of California-Davis in 1976 and postdoctoral studies from the Department of Hematology at Oakland Children's Hospital from 1976-1980. He is currently a professor as well as Dean of Research and Development of Chang Gung University in Taiwan. He has published over 130 scientific papers in reputable Journals such as Blood, JCI, Seminars in Hematology, British J of Hematology and Experimental Hematology. He is currently serving as an editorial board member of Free Radical Research and an associate editor of Biomedical Journal.

Abstract

Glucose 6-phosphate dehydrogenase (G6PD) is essential to maintain proper nicotinamide dinucleotide hydrogen phosphate(NADPH)levels and redox homeostasis. G6PD deficiency is associated with impaired glutathione (GSH) regeneration, and predisposes red blood cells (RBCs) to oxidative damage. The specific metabolomic pathways altered by G6PD deficiency, and the relation of these changes to the dysfunction of RBCs upon oxidant challenge are incompletely understood. In this study, we investigated the changes in global metabolism of RBCs in response to the oxidative challenge by diamide. Only minor differences were observed between the metabolome of untreated RBCs from that of normal and G6PD-deficient individuals. In contrast, significant changes in several biochemical pathways were found in G6PD-deficient RBCs, including changes in GSH metabolism, purine metabolism, and glycolysis. GSH depletion was accompanied by an exhaustive consumption in cellular energy due to a futile attempt to synthesize GSH by glutamyl cysteine synthetase. Accumulation of AMP and ADP led to AMPK activation and increased entry of glucose into glycolysis. However, oxidative modification of pyruvate kinase inhibited its activity leading to ineffective energy production. In addition, the diamide induced changes led to a loss in the ability of RBCs to deform under shear stress. This loss in RBC functionality was temporary and reversible in normal RBCs, but more severe and irreversible in G6PD-deficient RBCs. Taken together, these findings clearly demonstrate that metabolic anomalies account for diamide-induced dysfunctions of G6PD-deficient RBCs, and link the inability to counter oxidant insult by metabolism to the irreversible loss of functions of these cells .

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