Essential role for Nix in autophagic maturation of erythroid cells
Essential role for Nix in autophagic maturation of erythroid cells
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DOI：
10.1038/nature07006
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发表时间：
2008-07-10
期刊：
影响因子：
64.8
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Sandoval, Hector;Thiagarajan, Perumal;Wang, Jin
红系细胞在终末分化过程中经历去核和细胞器的去除（1-3）。尽管自噬被认为介导红系成熟的细胞器的消除（2-6），但该过程的分子机制仍不明确。在这里，我们报告了Bcl- 2家族成员Nix（也称为Bnip 3L）（7-9）在通过线粒体自噬调节红细胞成熟中的作用。Nix（-/-）小鼠出现贫血，伴成熟红细胞减少和红系前体细胞代偿性扩增。Nix（-/-）小鼠外周血中的红细胞表现出线粒体滞留和体内寿命缩短。虽然核糖体的清除在没有Nix的情况下正常进行，但线粒体进入自噬体进行清除是有缺陷的。Nix缺乏抑制线粒体膜电位（Δ Psi（m））的损失，并且用解偶联化学品或BH 3模拟物处理诱导Δ Psi（m）的损失，并恢复线粒体在Nix（-/-）红系细胞中的自噬体中的隔离。这些结果表明，Δ Psi（m）的Nix依赖性损失对于将线粒体靶向到自噬体中以在红细胞成熟期间清除是重要的，并且干扰该功能损害红细胞成熟并导致贫血。我们的研究也可能提供深入了解线粒体质量控制涉及线粒体自噬的分子机制。
Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation(1-3). Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation(2-6), the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl- 2 family member, Nix ( also called Bnip3L)(7-9), in the regulation of erythroid maturation through mitochondrial autophagy. Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix(-/-) mice exhibited mitochondrial retention and reduced lifespan in vivo. Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. Deficiency in Nix inhibited the loss of mitochondrial membrane potential (Delta Psi(m)), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of Delta Psi(m) and restored the sequestration of mitochondria into autophagosomes in Nix(-/-) erythroid cells. These results suggest that Nix- dependent loss of Delta Psi(m) is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythroid maturation and results in anaemia. Our study may also provide insights into molecular mechanisms underlying mitochondrial quality control involving mitochondrial autophagy.