Sequestration and autophagy of mitochondria do not cut proteins across the board.
Sequestration and autophagy of mitochondria do not cut proteins across the board.
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线粒体的隔离和自噬不会全面切割蛋白质。
DOI：
10.1073/pnas.1303921110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Youle,RichardJ
中科院分区：
文献类型：
--
作者：
Huang,Chiu-Hui;Lazarou,Michael;Youle,RichardJ
获得有害DNA突变或对蛋白质造成化学损伤的线粒体被自噬隔离和清除，据称是为了保持剩余细胞器的保真度。在PNAS中，Vincow等人证明了两种蛋白质，磷酸酶和张力蛋白同源诱导的推定激酶1（PINK 1）和Parkin，以家族性帕金森病的形式突变，在正常实验室环境中培养的果蝇体内促进线粒体自噬（mitophagy）（1）。因此，线粒体自噬似乎是一种常规和必要的管家活动，可能是必不可少的生存的某些神经元和肌肉细胞死亡的PINK 1和帕金突变苍蝇。这项工作还揭示了一个谜团，即一些线粒体呼吸链（RC）蛋白似乎被选择性地路由为自噬体降解，这一过程通常被认为是去除整个线粒体并不加区别地消除RC组分。已知果蝇中的PINK 1和Parkin在相同的途径中起作用，以防止多巴胺能神经元损失、飞行肌变性以及肿胀和功能障碍的线粒体的积累（2-4）。哺乳动物细胞培养研究还表明，PINK 1和帕金共同诱导化学或遗传受损线粒体的自噬（5-10）。不同的线粒体损伤产生相同的应激信号：膜电位的丧失使PINK 1在输入线粒体后从组成性降解转向在线粒体外膜上积累（5）。这种外膜位置允许PINK 1通过其激酶活性从细胞质中招募Parkin（一种E3泛素连接酶）到线粒体表面。一旦存在，帕金泛素化线粒体底物并激活线粒体的自噬体吞噬（11）。虽然PINK 1/Parkin介导的线粒体自噬已在培养细胞中得到证实，但PINK 1/Parkin是否在体内介导线粒体自噬仍不清楚，部分原因是难以测量线粒体自噬和线粒体周转率。Vincow et al. (1)使用定量质谱法来揭示整个动物体内蛋白质降解的全景。与野生型果蝇相比，帕金突变果蝇中线粒体蛋白的数量被鉴定为具有降低的周转率，并且这些与自噬缺陷（Atg 7突变）果蝇中显示降低的周转率的蛋白质显著相关。这表明
Mitochondria that acquire deleterious DNA mutations or sustain chemical damage to proteins are sequestered and cleared by autophagy, purportedly to maintain the fidelity of the remaining organelles. In PNAS, Vincow et al. demonstrate that two proteins, phosphatase and tensin homologinduced putative kinase 1 (PINK1) and Parkin, which are mutated in forms of familial parkinsonism, promote mitochondrial autophagy (mitophagy) in vivo in Drosophila raised in a normal laboratory environment (1). Thus, mitophagy appears to be a routine and necessary housekeeping activity that may be essential for survival of certain neurons and muscle cells that die in PINK1 and Parkin mutant flies. The work also uncovers a mystery that some mitochondrial respiratory chain (RC) proteins appear to be selectively routed for autophagosomal degradation, a process generally thought to remove entire mitochondria and indiscriminately eliminate RC components. PINK1 and Parkin in Drosophila are known to act in the same pathway to prevent dopaminergic neuron loss, flight muscle degeneration, and accumulation of swollen and dysfunctional mitochondria (2-4). Mammalian cell culture studies also illustrate that PINK1 and Parkin work together to induce autophagy of chemically or genetically impaired mitochondria (5-10). Diverse mitochondrial insults generate the same stress signal: a loss of membrane potential diverts PINK1 from constitutive degradation following import into mitochondria to accumulate on the outer mitochondrial membrane (5). This outer-membrane location permits PINK1 via its kinase activity to recruit Parkin, an E3 ubiquitin ligase, from the cytosol onto the surface of mitochondria. Once there, Parkin ubiquitinates mitochondrial substrates and activates autophagosome engulfment of mitochondria (11). Although PINK1/Parkin-mediated mitophagy has been demonstrated in cultured cells, whetherPINK1/Parkin mediates mitophagy in vivo remained unknown, in part, owing to the difficulty in measuring mitophagy and mitochondrial turnover rates. The study by Vincow et al.(1) uses quantitative mass spectrometry to reveal the panorama of protein degradation in whole animals. Scores of mitochondrial proteins were identified to have reduced turnover rates in Parkin mutant flies compared with wild-type flies, and these significantly correlate with proteins that display a reduced rate of turnover in autophagydeficient (Atg7 mutant) flies. This indicates