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Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy.

eLife (2018-04-21)
Gian-Luca McLelland, Thomas Goiran, Wei Yi, Geneviève Dorval, Carol X Chen, Nadine D Lauinger, Andrea I Krahn, Sepideh Valimehr, Aleksandar Rakovic, Isabelle Rouiller, Thomas M Durcan, Jean-François Trempe, Edward A Fon

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.

Product Number
Product Description

Anti-RHOT1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Anti-Mitofusin-2 (N-Terminal) antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Monoclonal Anti-β-Tubulin III antibody produced in mouse, clone SDL.3D10, ascites fluid
Anti-Actin Antibody, clone C4, ascites fluid, clone C4, Chemicon®
Anti-phospho-Ubiquitin (Ser65), from rabbit, purified by affinity chromatography