2. Academic Validation
  3. A glutamine metabolic switch supports erythropoiesis

A glutamine metabolic switch supports erythropoiesis

  • Science. 2024 Nov 15;386(6723):eadh9215. doi: 10.1126/science.adh9215.
Junhua Lyu # 1,  Zhimin Gu # 2,  Yuannyu Zhang # 1,  Hieu S Vu 1,  Christophe Lechauve 3,  Feng Cai 2,  Hui Cao 1,  Julia Keith 3,  Valentina Brancaleoni 4,  Francesca Granata 4,  Irene Motta 4 5,  Maria Domenica Cappellini 4,  Lily Jun-Shen Huang 6,  Ralph J DeBerardinis 2 7,  Mitchell J Weiss 3,  Min Ni 8,  Jian Xu 1
Affiliations

Affiliations

  • 1 Center of Excellence for Leukemia Studies, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2 Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • 5 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy.
  • 6 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8 Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • # Contributed equally.
PMID: 39541460 DOI: 10.1126/science.adh9215
Abstract

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 cell maturation. Glutamine synthetase (GS), one of the oldest functioning genes in evolution, is activated during erythroid maturation to detoxify ammonium generated from heme biosynthesis, which is up-regulated to support hemoglobin production. Loss of GS in mouse erythroid precursors caused ammonium accumulation and oxidative stress, impairing erythroid maturation and recovery from anemia. In β-thalassemia, GS activity is inhibited by protein oxidation, leading to glutamate and ammonium accumulation, whereas enhancing GS activity alleviates the metabolic and pathological defects. Our findings identify an evolutionarily conserved metabolic adaptation that could potentially be leveraged to treat common red blood cell disorders.

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