Burman Jonathon L, Pickles Sarah, Wang Chunxin, Sekine Shiori, Vargas Jose Norberto S, Zhang Zhe, Youle Alice M, Nezich Catherine L, Wu Xufeng, Hammer John A, Youle Richard J
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Molecular Cell Biology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
J Cell Biol. 2017 Oct 2;216(10):3231-3247. doi: 10.1083/jcb.201612106. Epub 2017 Sep 11.
Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1-Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing ΔOTC, it does not decrease the rate of ΔOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for ΔOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1-Parkin activity.
在线粒体基质中，蛋白质聚集激活线粒体未折叠蛋白反应以及由PINK1 - Parkin介导的线粒体自噬，以减轻蛋白质毒性。我们探究自噬如何清除线粒体内的蛋白质聚集体以及线粒体裂变在线粒体自噬中的作用。我们发现，放线菌酮诱导线粒体蛋白质毒性后，PINK1会将Parkin招募到线粒体亚结构域上，并且PINK1会将Parkin招募到线粒体定位的突变型鸟氨酸转氨甲酰酶（ΔOTC）的局部错误折叠聚集体附近。Parkin与泛素、视黄醛结合蛋白和LC3共定位于含有错误折叠蛋白聚集灶的极化线粒体上。尽管抑制Drp1介导的线粒体裂变会抑制含有ΔOTC的线粒体亚结构域的分离，但它并不会降低ΔOTC的清除率。相反，Drp1的缺失增强了Parkin向融合线粒体网络的募集以及线粒体自噬的速率，同时降低了线粒体自噬过程中对ΔOTC的选择性。这些结果与一个新模型一致，即裂变并非促进线粒体自噬，而是保护健康的线粒体结构域不被不受控制的PINK1 - Parkin活性清除。
