The formation of new red blood cells (RBC) (erythropoiesis) has served as a paradigm for understanding cellular differentiation and developmental control of gene expression. The metabolic regulation of this complex, coordinated process remains poorly understood. Each step of erythropoiesis, including lineage specification of hematopoietic stem cells, proliferation, differentiation, and terminal maturation into highly specialized oxygen-carrying cells, has unique metabolic requirements. Developing erythrocytes in mammals are also characterized by unique metabolic events such as loss of mitochondria with switch to glycolysis, ejection of nucleus and organelles, high-level heme and hemoglobin synthesis, and antioxidant requirement to protect hemoglobin molecules. Genetic defects in metabolic enzymes, including pyruvate kinase and glucose-6-phosphate dehydrogenase, cause common erythrocyte disorders, whereas other inherited disorders such as sickle cell disease and β-thalassemia display metabolic abnormalities associated with disease pathophysiology. Here we describe recent discoveries on the metabolic control of RBC formation and function, highlight emerging concepts in understanding the erythroid metabolome, and discuss potential therapeutic benefits of targeting metabolism for RBC disorders.

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红细胞发育和疾病的代谢调节

新红细胞 (RBC)（红细胞生成）的形成已成为理解细胞分化和基因表达发育控制的范例。这一复杂、协调的过程的代谢调节仍然知之甚少。红细胞生成的每个步骤，包括造血干细胞的谱系规范、增殖、分化和最终成熟为高度特化的携氧细胞，都有独特的代谢要求。哺乳动物发育中的红细胞还具有独特的代谢事件，例如线粒体丧失并转为糖酵解、细胞核和细胞器的排出、高水平血红素和血红蛋白合成，以及保护血红蛋白分子的抗氧化剂需求。代谢酶（包括丙酮酸激酶和葡萄糖-6-磷酸脱氢酶）的遗传缺陷会导致常见的红细胞疾病，而镰状细胞病和β-地中海贫血等其他遗传性疾病则表现出与疾病病理生理学相关的代谢异常。在这里，我们描述了关于红细胞形成和功能的代谢控制的最新发现，强调了理解红细胞代谢组的新兴概念，并讨论了针对红细胞疾病的靶向代谢的潜在治疗益处。