An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism
Pedro González‐Menéndez, Manuela Romano, Hongxia Yan, Ruhi Deshmukh, Julien Papoin, Leal Oburoglu, Marie Daumur, Anne‐Sophie Dumé, Ira Phadke, Cédric Mongellaz, Xiaoli Qu, Phuong-Nhi Bories, Michaëla Fontenay, Xiuli An, Valérie Dardalhon, Marc Sitbon, Valérie S. Zimmermann, Patrick G. Gallagher, Saverio Tardito, Lionel Blanc, Narla Mohandas, Naomi Taylor, Sandrina Kinet
Abstract
The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) 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 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results 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 increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.