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

被引:305
作者
McLelland, Gian-Luca [1 ,2 ,7 ]
Goiran, Thomas [1 ,2 ]
Yi, Wei [1 ,2 ]
Dorval, Genevieve [1 ,2 ,3 ]
Chen, Carol X. [1 ,2 ,3 ]
Lauinger, Nadine D. [1 ,2 ,3 ]
Krahn, Andrea I. [1 ,2 ]
Valimehr, Sepideh [4 ]
Rakovic, Aleksander [5 ]
Rouiller, Isabelle [4 ]
Durcan, Thomas M. [1 ,2 ,3 ]
Trempe, Jean-Francois [6 ]
Fon, Edward A. [1 ,2 ,3 ]
机构
[1] McGill Univ, Montreal Neurol Inst, McGill Parkinson Program, Montreal, PQ, Canada
[2] McGill Univ, Montreal Neurol Inst, Neurodegenerat Dis Grp, Montreal, PQ, Canada
[3] McGill Univ, Montreal Neurol Inst, iPSC CRISPR Platform, Montreal, PQ, Canada
[4] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
[5] Univ Lubeck, Inst Neurogenet, Lubeck, Germany
[6] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
[7] Netherlands Canc Inst, Amsterdam, Netherlands
基金
加拿大健康研究院;
关键词
MIDBRAIN DOPAMINE NEURONS; SNARE SYNTAXIN 17; ENDOPLASMIC-RETICULUM; MITOFUSIN; PHOSPHORYLATED UBIQUITIN; PARKINSONS-DISEASE; PINK1; AUTOPHAGY; ACTIVATION; COMPLEX;
D O I
10.7554/eLife.32866
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:35
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