Mitochondria in the Regulation of Terminal Erythropoiesis

项目摘要/摘要 每天大量生产2000亿个红细胞(RBC)需要显著的协调 红系细胞的分化和成熟，与红系去核有关。 控制终末红系细胞成熟和去核的调节机制的变化是 与红系和其他疾病有牵连。对这些过程的有限了解一直是一个障碍 以治疗干预和大规模生产红细胞。我们长期以来对转录因子的关注 FOXO_3是终末红细胞生成的中央调节因子，它使我们发现线粒体是关键的和 这些过程中的动态调节器。我们最近发现线粒体正在积极地调节 红系细胞去核。值得注意的是，我们发现了外源性丙酮酸--一种糖酵解的产物--但不是原位的。 通过糖酵解产生丙酮酸，为线粒体提供燃料，并维持红系去核，表明 外源性丙酮酸在这一过程中发挥了意想不到的重要作用。我们正在进行的研究扩展到 这些发现表明，线粒体的功能不依赖于ATP，也与线粒体有关 包括清除在内的通路可能是终末期红细胞生成的中心，它们的变化可能与 疾病。我们的联合研究提出了线粒体可能整合和协调几个 去核前和去核过程中红细胞成熟所必需的功能。要进一步解决 线粒体在终末期红细胞生成中的作用，我们将完成以下工作：(目标1)我们将研究 线粒体清除对红系细胞成熟和去核的贡献；(目标2)我们将 探讨线粒体网络和形态对红系细胞调控的作用 成熟与去核，以及(目标3)我们将解决丙酮酸介导的特定途径 终末红细胞生成过程中的线粒体。这些研究可能揭示一种新的红系发病机制 细胞成熟和去核，并产生关键信息，以开发新的方法 治疗和提高红细胞产量。

PROJECT SUMMARY/ABSTRACT The massive daily production of 200 billion red blood cells (RBCs) requires a remarkable coordination of erythroid cell differentiation and maturation, with processes that are implicated in erythroid enucleation. Alterations in regulatory mechanisms that control the terminal erythroid cell maturation and enucleation are implicated in erythroid and other disorders. Limited knowledge of these processes have been an impediment to therapy interventions and large-scale RBC production. Our long-standing focus on the transcription factor Foxo3 that is a central regulator of terminal erythropoiesis led us to identifying mitochondria as critical and dynamic regulators in these processes. We recently showed that mitochondria are actively regulating erythroid cell enucleation. Notably, we found exogenous pyruvate – a product of glycolysis – but not in situ produced pyruvate via glycolysis fuel mitochondria and sustains erythroid enucleation suggesting an unanticipated and significant function for exogenous pyruvate in this process. Our ongoing studies extend these findings and suggest that ATP-independent mitochondrial functions as well as mitochondrial-related pathways including clearance may be central to terminal erythropoiesis and their alterations implicated in disease. Our combined studies raise the possibility that mitochondria might integrate and coordinate several functions necessary for erythroid cell maturation prior and during enucleation. To further address mitochondrial functions in terminal erythropoiesis, we will accomplish the following: (Aim 1) we will investigate the contribution of mitochondrial clearance to erythroid cell maturation vs. enucleation; (Aim 2) we will investigate the contribution of mitochondrial network and morphology to the regulation of erythroid cell maturation vs. enucleation, and (Aim 3) we will address the specific pyruvate-mediated pathway that fuel mitochondria during terminal erythropoiesis. These studies are likely to expose a new mechanism of erythroid cell maturation and enucleation and to generate critical information for developing new means towards novel therapies and improving RBC production.