Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation
Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation
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DOI：
10.1182/blood-2008-04-151639
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发表时间：
2009-07-02
期刊：
影响因子：
20.3
通讯作者：
Ney, Paul A.
中科院分区：
文献类型：
--
作者：
Zhang, Ji;Randall, Mindy S.;Ney, Paul A.
线粒体清除是一个众所周知但知之甚少的生物学过程，而网织红细胞经历了线粒体程序性清除，为研究这一现象提供了一个有用的模型。在超微结构水平上，线粒体清除类似于自噬相关的过程；然而，自噬在线粒体清除中的作用尚未确定。在这里，我们提供了基因证据，证明最初在酵母中发现的自噬途径参与了网织红细胞对线粒体的清除。ATG7是一种自噬蛋白，也是一种E1样酶，这是双泛素样偶联途径的活性所必需的。ATG7是ATG12与ATG5、ATG8与磷脂酰乙醇胺(PE)结合所必需的，也是自噬小体形成所必需的。在缺乏ATG7的情况下，网织红细胞对线粒体的清除减少，但不是完全阻断。ATG8的哺乳动物同源物在ATG7(-/-)红系细胞中没有修饰，这表明典型的自噬途径是不活跃的。因此，线粒体清除既受自噬依赖机制的调节，也受自噬独立机制的调节。此外，在野生型细胞中消除极化之前的线粒体，在培养的ATG7(-/-)网织红细胞中保持极化。这表明线粒体去极化是网织红细胞自噬小体形成的结果，而不是原因。(血。2009；114：157-164)
Mitochondrial clearance is a well recognized but poorly understood biologic process, and reticulocytes, which undergo programmed mitochondrial clearance, provide a useful model to study this phenomenon. At the ultrastructural level, mitochondrial clearance resembles an autophagy-related process; however, the role of autophagy in mitochondrial clearance has not been established. Here we provide genetic evidence that autophagy pathways, initially identified in yeast, are involved in mitochondrial clearance from reticulocytes. Atg7 is an autophagy protein and an E1-like enzyme, which is required for the activity of dual ubiquitin-like conjugation pathways. Atg7 is required for the conjugation of Atg12 to Atg5, and Atg8 to phosphatidylethanolamine (PE), and is essential for autophagosome formation. In the absence of Atg7, mitochondrial clearance from reticulocytes is diminished but not completely blocked. Mammalian homologs of Atg8 are unmodified in Atg7(-/-) erythroid cells, indicating that canonical autophagy pathways are inactive. Thus, mitochondrial clearance is regulated by both autophagy-dependent and -independent mechanisms. In addition, mitochondria, which depolarize in wild-type cells before elimination, remain polarized in Atg7(-/-) reticulocytes in culture. This suggests that mitochondrial depolarization is a consequence rather than a cause of autophagosome formation in reticulocytes. (Blood. 2009; 114:157-164)