Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy.
Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy.
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作者：
McLelland GL;Goiran T;Yi W;Dorval G;Chen CX;Lauinger ND;Krahn AI;Valimehr S;Rakovic A;Rouiller I;Durcan TM;Trempe JF;Fon EA
尽管它们作为信号传导枢纽的重要性，但线粒体质量控制途径中的Escheria-ER接触位点的功能仍然未被探索。在这里，我们描述了一种机制，Mfn 2，一个ESTA-ER系链，门线粒体的PINK 1和parkin的自噬营业额。线粒体-ER并置在线粒体自噬期间被破坏，并且减少线粒体-ER接触增加线粒体降解的速率。从机制上讲，parkin/PINK 1催化Mfn 2磷酸化的快速爆发，以触发Mfn 2复合物从线粒体外膜的p97依赖性解体，使线粒体与ER解离。我们还证明了p97对线粒体自噬的促进作用的主要部分是上位性的Mfn 2，并促进了其他帕金底物，如VDAC 1的可用性。最后，我们在无细胞测定中重建了这些因子对Mfn 2和VDAC 1泛素化的作用。我们发现，ESTA-ER束缚抑制线粒体自噬，并描述了一个parkin/PINK 1依赖的机制，调节ESTA-ER接触位点的破坏。
Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites.