Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
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DOI：
10.1091/mbc.e16-07-0545
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发表时间：
2017-03-01
影响因子：
3.3
通讯作者：
Koehler CM
中科院分区：
文献类型：
--
作者：
Steffen J;Vashisht AA;Wan J;Jen JC;Claypool SM;Wohlschlegel JA;Koehler CM
SCL25A46是一种定位于外膜的线粒体载体蛋白。突变L341P通过泛素-蛋白酶体系统导致SLC25A46的快速降解，而不依赖于激活的应激途径，包括有丝分裂和细胞凋亡。SLC25A46调节Mfn1/2的寡聚和线粒体动力学。SCL25A46是一种线粒体载体蛋白，出人意料地定位于外膜，与Ugo1有较远的亲缘关系。在这里，我们证明了SLC25A46的子集与线粒体动力学组件和MICOS复合体相互作用。SLC25A46的低表达导致线粒体上Mfn1和Mfn2的稳定性增加和寡聚化，促进线粒体的高融合。L341P的突变导致SLC25A46的快速降解，表现为一种罕见的疾病，桥小脑发育不全。E3泛素连接酶木兰和March5协调SLC25A46 L341P的泛素化，通过P97和蛋白酶体的有组织活动导致降解。线粒体膜外相关的降解通常与细胞凋亡或一种称为有丝分裂的特殊类型的自噬有关，而SLC25A46的降解独立于外膜应激途径的激活而起作用。因此，SLC25A46是线粒体动力学中的一个新成分，它作为Mfn1/2寡聚的调节因子。此外，SLC25A46选择性地从外膜降解，不依赖于有丝分裂和细胞凋亡，为外膜蛋白降解的机制研究提供了一个框架。
SCL25A46 is a mitochondrial carrier protein that localizes to the outer membrane. Mutation L341P causes rapid degradation of SLC25A46 by the ubiquitin-proteasome system, independent of activated stress pathways, including mitophagy and apoptosis. SLC25A46 regulates oligomerization of MFN1/2 and mitochondrial dynamics. 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.