Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics.
Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics.
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DOI：
10.3389/fcell.2020.592035
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发表时间：
2020
影响因子：
5.5
通讯作者：
Elorza AA
中科院分区：
文献类型：
--
作者：
Gonzalez-Ibanez AM;Ruiz LM;Jensen E;Echeverria CA;Romero V;Stiles L;Shirihai OS;Elorza AA
红细胞生成是最强大的细胞分化和增殖系统，每天产生102 × 1011个细胞。在这个微调过程中，造血干细胞（HSC）产生红系祖细胞，其增殖并成熟为红细胞。在红细胞生成过程中，线粒体被重新编程以驱动分化过程，然后最终被线粒体自噬消除。在红细胞生成中，线粒体动力学（MtDy）预计是一个关键的调控点，以前没有描述过。我们描述了一种特定的MtDy模式发生在EPO诱导的人CD34+细胞的人红细胞生成中，其特征主要是早期阶段的线粒体融合，随后是晚期阶段的分裂。融合蛋白MFN1和分裂蛋白FIS1在红细胞生成过程中起关键作用。FIS1的过度表达（获得裂变）导致的线粒体网的碎片化导致血红蛋白生物合成的抑制和红细胞分化的停滞，使细胞处于未成熟的分化阶段。与对照细胞相比，这些细胞显示出特定的线粒体特征，例如圆形和大线粒体形态的增加、低线粒体膜电位、呼吸复合物II和IV的表达的下降以及ROS的增加。有趣的是，用线粒体渗透性转换孔（mPTP）抑制剂环孢菌素A处理可以挽救线粒体形态、血红蛋白生物合成和红细胞生成。这项工作中提出的研究揭示了MtDy作为控制红细胞分化的热点，其可能通过调节mPTP向下游发出代谢重编程的信号。
Erythropoiesis is the most robust cellular differentiation and proliferation system, with a production of ∼2 × 1011 cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) are expected to be a key regulatory point that has not been described previously. We described that a specific MtDy pattern occurs in human erythropoiesis from EPO-induced human CD34+ cells, characterized predominantly by mitochondrial fusion at early stages followed by fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondrial morphology, low mitochondrial membrane potential, a drop in the expression of the respiratory complexes II and IV and increased ROS. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor, cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work reveal MtDy as a hot spot in the control of erythroid differentiation, which might signal downstream for metabolic reprogramming through regulation of the mPTP.
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影响因子：
4.6
作者：
Bigarella, Carolina L.;Liang, Raymond;Ghaffari, Saghi
通讯作者：
Ghaffari, Saghi
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
5
作者：
Bernardi, Paolo;Di Lisa, Fabio
通讯作者：
Di Lisa, Fabio
影响因子：
5.3
作者：
Jheng, Huei-Fen;Tsal, Pei-Jane;Tsai, Yau-Sheng
通讯作者：
Tsai, Yau-Sheng
影响因子：
46.9
作者：
Giarratana, MC;Kobari, L;Douay, L
通讯作者：
Douay, L