Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron–sulfur proteins, including Iron Regulatory Protein 1 (IRP1). These processes are tightly regulated to prevent both excess and insufficient levels of iron and heme precursors. Crosstalk between the heme and iron–sulfur synthesizing pathways has been demonstrated to serve as a regulatory feedback mechanism. The activity of δ-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme of heme biosynthesis, is a fundamental node of this regulation. Recently, the mitochondrial unfoldase, ClpX, has received attention as a novel key player that modulates this step in heme biogenesis, implicating a role in the pathophysiology of anemic diseases. This chapter reviews the canonical pathways in intracellular iron and heme trafficking and recent findings of iron and heme metabolism in vertebrate red cells. A discussion of the molecular approaches to studying iron and heme transport is provided to highlight opportunities for revealing therapeutic targets.

中文翻译：

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发育中的成红细胞中细胞内铁和血红素的运输和代谢

脊椎动物的红血球（RBC）通过称为红细胞生成的过程从人骨髓中的成红细胞中产生。铁的摄取是至关重要的标志，对于分化的成血红细胞中血红素的生物合成至关重要，所述成血红细胞专门用于产生血红蛋白。细胞内转运蛋白，分子伴侣和循环激素的网络促进了促红细胞生成。细胞内铁靶向线粒体，并结合到卟啉环中形成血红素和胞质铁硫蛋白，包括铁调节蛋白1（IRP1）。严格控制这些过程，以防止铁和血红素前体的过量和不足。血红素和铁硫合成途径之间的串扰已被证明是一种监管反馈机制。血红素生物合成的第一个也是限速酶δ-氨基乙酰丙酸合酶（ALAS）的活性是该调节的基本节点。最近，线粒体解折叠酶ClpX作为调节血红素生物发生中这一步骤的新型关键角色而受到关注，这暗示着贫血疾病的病理生理学中的作用。本章回顾了细胞内铁和血红素运输中的典型途径，以及脊椎动物红细胞中铁和血红素代谢的最新发现。提供了研究铁和血红素转运的分子方法的讨论，以突出揭示治疗靶标的机会。作为调节血红素生物发生中这一步骤的新型关键参与者，已受到关注，这在贫血疾病的病理生理学中起作用。本章回顾了细胞内铁和血红素运输中的典型途径，以及脊椎动物红细胞中铁和血红素代谢的最新发现。提供了研究铁和血红素转运的分子方法的讨论，以突出揭示治疗靶标的机会。作为调节血红素生物发生中这一步骤的新型关键参与者，已受到关注，这在贫血疾病的病理生理学中起作用。本章回顾了细胞内铁和血红素运输中的典型途径，以及脊椎动物红细胞中铁和血红素代谢的最新发现。提供了研究铁和血红素转运的分子方法的讨论，以突出揭示治疗靶标的机会。