A glutamine metabolic switch supports erythropoiesis

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-11-15 DOI:10.1126/science.adh9215

Junhua Lyu, Zhimin Gu, Yuannyu Zhang, Hieu S. Vu, Christophe Lechauve, Feng Cai, Hui Cao, Julia Keith, Valentina Brancaleoni, Francesca Granata, Irene Motta, Maria Domenica Cappellini, Lily Jun-Shen Huang, Ralph J. DeBerardinis, Mitchell J. Weiss, Min Ni, Jian Xu

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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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谷氨酰胺代谢开关支持红细胞生成

在发育过程中，代谢需求各不相同，而我们对代谢活动如何影响细胞特化的了解还不全面。在这里，我们描述了红细胞成熟所需的谷氨酰胺从分解到合成的转变。谷氨酰胺合成酶（GS）是进化过程中最古老的功能基因之一，它在红细胞成熟过程中被激活，以解毒血红素生物合成过程中产生的氨，而血红素生物合成过程被上调以支持血红蛋白的生成。小鼠红细胞前体中 GS 的缺失会导致铵积累和氧化应激，影响红细胞的成熟和贫血的恢复。在β-地中海贫血症中，GS的活性受到蛋白质氧化的抑制，导致谷氨酸和铵的积累，而增强GS的活性则能缓解代谢和病理缺陷。我们的研究发现了一种进化保守的代谢适应性，有可能被用来治疗常见的红细胞疾病。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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