Steffen Janos, Vashisht Ajay A, Wan Jijun, Jen Joanna C, Claypool Steven M, Wohlschlegel James A, Koehler Carla M
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
Mol Biol Cell. 2017 Mar 1;28(5):600-612. doi: 10.1091/mbc.E16-07-0545. Epub 2017 Jan 5.
SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.
SCL25A46是一种线粒体载体蛋白，令人惊讶的是它定位于外膜，并且与Ugo1有较远的亲缘关系。在这里我们表明，SLC25A46的一个亚群与线粒体动力学成分和MICOS复合体相互作用。SLC25A46表达的降低导致MFN1和MFN2在线粒体上的稳定性和寡聚化增加，促进线粒体过度融合。L341P处的突变导致SLC25A46快速降解，这表现为一种罕见疾病，即脑桥小脑发育不全。E3泛素连接酶MULAN和MARCH5协调SLC25A46 L341P的泛素化，导致其被P97和蛋白酶体的有组织活动降解。而线粒体外膜相关降解通常与细胞凋亡或一种称为线粒体自噬的特殊自噬类型相关，SLC（此处原文有误，应该是SLC25A46）25A46的降解独立于外膜应激途径的激活而发生。因此，SLC25A46是线粒体动力学中的一个新成分，可以作为MFN1/2寡聚化的调节因子。此外，SLC25A46从外膜被选择性降解，独立于线粒体自噬和细胞凋亡，为外膜蛋白蛋白水解的机制研究提供了一个框架。
