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

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Abstract

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.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all Figures.

Article and author information

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Gian-Luca McLelland

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Thomas Goiran

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Wei Yi

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Geneviève Dorval

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Carol X Chen

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Nadine D Lauinger

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Andrea I Krahn

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

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The authors declare that no competing interests exist.
Sepideh Valimehr

Department of Anatomy and Cell Biology, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Aleksandar Rakovic

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

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The authors declare that no competing interests exist.
Isabelle Rouiller

Department of Anatomy and Cell Biology, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Thomas M Durcan

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Jean-François Trempe

Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada

Competing interests
The authors declare that no competing interests exist.
Edward A Fon

McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada

For correspondence
ted.fon@mcgill.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5520-6239

Funding

Canadian Institutes of Health Research (Canada Graduate Scholarship)

Gian-Luca McLelland

Canadian Institutes of Health Research (Foundation Grant)

Edward A Fon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.