TY - JOUR TI - Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy AU - McLelland, Gian-Luca AU - Goiran, Thomas AU - Yi, Wei AU - Dorval, Geneviève AU - Chen, Carol X AU - Lauinger, Nadine D AU - Krahn, Andrea I AU - Valimehr, Sepideh AU - Rakovic, Aleksandar AU - Rouiller, Isabelle AU - Durcan, Thomas M AU - Trempe, Jean-François AU - Fon, Edward A A2 - Dikic, Ivan VL - 7 PY - 2018 DA - 2018/04/20 SP - e32866 C1 - eLife 2018;7:e32866 DO - 10.7554/eLife.32866 UR - https://doi.org/10.7554/eLife.32866 AB - 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. KW - mitochondria KW - contact site KW - mitophagy KW - Parkinson's disease KW - ubiquitination JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -