Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy
Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy
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DOI：
10.1093/jb/mvy077
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发表时间：
2019-01-01
影响因子：
2.7
通讯作者：
Takeda, Kohsuke
中科院分区：
文献类型：
--
作者：
Yamaguchi, Ayane;Ishikawa, Hayate;Takeda, Kohsuke
PGAM 5是存在于线粒体中的一种独特类型的蛋白磷酸酶。已显示其通过其跨膜结构域存在于线粒体内膜中，并且在线粒体功能障碍时在跨膜结构域内被切割。然而，它的亚线粒体定位仍然存在争议;许多研究人员声称，PGAM 5定位于外线粒体膜的基础上发现，PGAM 5与许多细胞质蛋白。在这里，我们发现，裂解的PGAM 5线粒体自噬，线粒体特异性自噬的选择性形式，从线粒体中释放，并在稳定表达E3泛素连接酶帕金蛋白的HeLa细胞中的蛋白酶体抑制剂的释放被抑制。然而，缺乏帕金与线粒体自噬诱导剂的亲本HeLa细胞的治疗引起PGAM 5裂解，但没有导致其从线粒体释放。因此，切割的PGAM 5似乎是从线粒体释放依赖于蛋白酶体介导的线粒体自噬过程中的外膜破裂，这已经被证明之前自噬介导的整个线粒体的降解。这项研究表明，PGAM 5传感线粒体内膜中的线粒体功能障碍，并作为一种信号传导中间体，调节细胞对线粒体应激的反应，当其从线粒体裂解和释放时。
PGAM5 is a unique type of protein phosphatase that exists in mitochondria. It has been shown to exist in the inner mitochondrial membrane through its transmembrane domain and to be cleaved within the transmembrane domain upon mitochondrial dysfunction. However, its submitochondrial localization remains controversial; many researchers claim that PGAM5 localizes to the outer mitochondrial membrane based on the findings that PGAM5 associates with many cytoplasmic proteins. Here, we found that cleaved PGAM5 was released from mitochondria during mitophagy, a selective form of autophagy specific for mitochondria, and that the release was inhibited by proteasome inhibitors in HeLa cells stably expressing the E3 ubiquitin ligase Parkin. However, treatment of parental HeLa cells lacking Parkin with mitophagy-inducing agents caused PGAM5 cleavage but did not cause its release from mitochondria. Thus, cleaved PGAM5 appears to be released from mitochondria depending on proteasome-mediated rupture of the outer membrane during mitophagy, which has been previously shown to precede autophagy-mediated degradation of whole mitochondria. This study suggests that PGAM5 senses mitochondrial dysfunction in the inner mitochondrial membrane and serves as a signalling intermediate that regulates the cellular response to mitochondrial stress upon its cleavage and release from mitochondria.