McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada
Thomas Goiran
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada
Wei Yi
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada
Geneviève Dorval
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada; iPSC-CRISPR Platform, Montreal Neurological Institute, McGill University, Montreal, Canada
Carol X Chen
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada; iPSC-CRISPR Platform, Montreal Neurological Institute, McGill University, Montreal, Canada
Nadine D Lauinger
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada; iPSC-CRISPR Platform, Montreal Neurological Institute, McGill University, Montreal, Canada
Andrea I Krahn
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada
Sepideh Valimehr
Department of Anatomy & Cell Biology, McGill University, Montreal, Canada
Aleksandar Rakovic
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Isabelle Rouiller
Department of Anatomy & Cell Biology, McGill University, Montreal, Canada
Thomas M Durcan
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada; iPSC-CRISPR Platform, Montreal Neurological Institute, McGill University, Montreal, Canada
Jean-François Trempe
Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Canada; Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada; iPSC-CRISPR Platform, Montreal Neurological Institute, McGill University, Montreal, Canada
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.
