A glutamine metabolic switch supports erythropoiesis

• DOI: 10.1126/science.adh9215
• Publication Date: 2024-11-14T19:00:03Z
• Authors: Junhua Lyu; Zhimin Gu; Yuannyu Zhang; Hieu S. Vu; Christophe Lechauve; Feng Cai; Hui Cao; Julia Keith; Valentina Brancal...; Francesca Granata; Irene Motta; Maria Domenica Ca...; Lily Jun-Shen Huang; Ralph J. DeBerard...; Mitchell J. Weiss; Min Ni; Jian Xu
• Keywords: Catabolism; Metabolic pathway; Ineffective erythropoiesis

Metabolic requirements vary during development, and our understanding of how metabolic activity influences cell specialization is incomplete. Here, we describe a switch from glutamine catabolism to synthesis required for erythroid maturation. Glutamine synthetase (GS), one the oldest functioning genes in evolution, activated maturation detoxify ammonium generated heme biosynthesis, which up-regulated support hemoglobin production. Loss GS mouse precursors caused accumulation oxidative stress, impairing recovery anemia. In β-thalassemia, inhibited by protein oxidation, leading glutamate accumulation, whereas enhancing alleviates pathological defects. Our findings identify an evolutionarily conserved adaptation that could potentially be leveraged treat common red blood disorders.