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An IDH1-Vitamin C Crosstalk Drives Human Erythroid Development By Inhibiting Pro-Oxidant Mitochondrial Metabolism
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- The metabolic changes controlling the step-wise differentiation of human stem and progenitor cells (HSPC) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase (IDH1) plays a central role in this process. IDH1 downregulation augmented mitochondrial oxidation of αKG and inhibited reticulocyte generation. Furthermore, IDH1-knockdown resulted in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis –– oxidized ascorbate increased mitochondrial superoxide and significantly exacerbated the abnormal erythroblast phenotype of IDH1-downregulated progenitors whereas vitamin C, scavenging reactive oxygen species and reprogramming mitochondrial metabolism, rescued erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi...........95cc86f585b09affa73a326d86edfb87