Enhanced BPGM/2,3-DPG pathway activity suppresses glycolysis in hypoxic astrocytes via FIH-1 and TET2.

Guoji E, Binda Sun, Bao Liu, Gang Xu, Shu He, Yu Wang, Lan Feng, Hannan Wei, Jianyang Zhang, Jian Chen, Yuqi Gao, Erlong Zhang

Brain research bulletin 2023 Jan

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Bisphosphoglycerate mutase (BPGM) is expressed in human erythrocytes and responsible for the production of 2,3-bisphosphoglycerate (2,3-DPG). However, the expression and role of BPGM in other cells have not been reported. In this work, we found that BPGM was significantly upregulated in astrocytes upon acute hypoxia, and the role of this phenomenon will be clarified in the following report. The mRNA and protein expression levels of BPGM and the content of 2,3-DPG with hypoxia treatment were determined in vitro and in vivo. Furthermore, glycolysis was evaluated upon in hypoxic astrocytes with BPGM knockdown and in normoxic astrocytes with BPGM overexpression or 2,3-DPG treatment. To investigate the mechanism by which BPGM/2,3-DPG regulated glycolysis in hypoxic astrocytes, we detected the expression of HIF-1α, FIH-1 and TET2 with silencing or overexpression of BPGM and 2,3-DPG treatment. The expression of glycolytic genes and the capacity of lactate markedly increased with 6 h, 12 h, 24 h, 36 h and 48 h 1 % O2 hypoxic treatment in astrocytes. The expression of BPGM was upregulated, and the production of 2,3-DPG was accelerated upon hypoxia. Moreover, when BPGM expression was knocked down, glycolysis was promoted in HEB cells. However, overexpression of BPGM and addition of 2,3-DPG to the cellular medium in normoxic cells could downregulate glycolytic genes. Furthermore, HIF-1α and TET2 exhibited higher expression levels and FIH-1 showed a lower expression level upon BPGM silencing, while these changes were reversed under BPGM overexpression and 2,3-DPG treatment. Our study revealed that the BPGM/2,3-DPG pathway presented a suppressive effect on glycolysis in hypoxic astrocytes by negatively regulating HIF-1α and TET2. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Guoji E, Binda Sun, Bao Liu, Gang Xu, Shu He, Yu Wang, Lan Feng, Hannan Wei, Jianyang Zhang, Jian Chen, Yuqi Gao, Erlong Zhang. Enhanced BPGM/2,3-DPG pathway activity suppresses glycolysis in hypoxic astrocytes via FIH-1 and TET2. Brain research bulletin. 2023 Jan;192:36-46