Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy
| Autor: | Edward A. Fon, Thomas M. Durcan, Geneviève Dorval, Wei Yi, Carol X.-Q. Chen, Thomas Goiran, Gian-Luca McLelland, Sepideh Valimehr, Nadine D Lauinger, Aleksandar Rakovic, Jean-François Trempe, Andrea I Krahn, Isabelle Rouiller |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
QH301-705.5 Parkinson's disease Science MFN2 Mitochondrial Degradation PINK1 Mitochondrion ubiquitination General Biochemistry Genetics and Molecular Biology Parkin 03 medical and health sciences contact site Mitophagy Biology (General) General Immunology and Microbiology Chemistry General Neuroscience Autophagy General Medicine Cell biology mitochondria mitophagy 030104 developmental biology Medicine VDAC1 |
| Zdroj: | eLife, Vol 7 (2018) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.32866 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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