Mitochondrial quality control by the ubiquitin-proteasome system
Mitochondrial quality control by the ubiquitin-proteasome system
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DOI：
10.1042/bst0391509
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发表时间：
2011-10-01
影响因子：
3.9
通讯作者：
Rutter, Jared
中科院分区：
文献类型：
--
作者：
Taylor, Eric B.;Rutter, Jared
线粒体具有多种功能，对维持细胞内环境平衡至关重要，它们的功能失调会导致疾病。一些证据表明，存在一条调控线粒体蛋白质质量控制的MAD(线粒体相关降解)途径。线粒体内的蛋白质可能被逆行移位到线粒体外膜(OMM)，多个E3泛素连接酶位于OMM处，抑制蛋白酶体导致泛素化蛋白在OMM处聚集。CDC48(细胞分裂周期42)/p97与ERAD[ER(内质网)相关降解]类似，被招募到应激的线粒体上，从OMM中提取泛素化的蛋白质，并将泛素化的蛋白质提供给蛋白酶体进行降解。最近的研究为UPS(泛素-蛋白酶体系统)与OMM的相互作用提供了机械性的见解。在酵母中，Vms1[VCP(包含Valosin的蛋白)(P97)/CDC48相关的线粒体应激反应1]蛋白将CDC48/p97招募到OMM。在哺乳动物系统中，E3泛素连接酶PARKIN调节CDC48/p97向线粒体的募集、随后的线粒体蛋白降解和线粒体自噬。Vms1或Parkin系统的破坏会导致线粒体泛素化蛋白的过度积累，从而导致线粒体功能障碍。新出现的MAD途径对于维持细胞和生物体的生存能力是重要的。
Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondria-associated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle 42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights into the interaction of the UPS (ubiquitin-proteasome system) with the OMM. In yeast, Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97 to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy. Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the maintenance of cellular and therefore organismal viability.