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

  1. Gian-Luca McLelland
  2. Thomas Goiran
  3. Wei Yi
  4. Geneviève Dorval
  5. Carol X Chen
  6. Nadine D Lauinger
  7. Andrea I Krahn
  8. Sepideh Valimehr
  9. Aleksandar Rakovic
  10. Isabelle Rouiller
  11. Thomas M Durcan
  12. Jean-François Trempe
  13. Edward A Fon  Is a corresponding author
  1. Montreal Neurological Institute and Hospital, McGill University, Canada
  2. McGill University, Canada
  3. University of Lübeck, Germany

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.

Data availability

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

Author details

  1. 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.
  2. Thomas Goiran

    McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Wei Yi

    McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Geneviève Dorval

    McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. 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.
  6. 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.
  7. Andrea I Krahn

    McGill Parkinson Program, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Sepideh Valimehr

    Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Aleksandar Rakovic

    Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Isabelle Rouiller

    Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. 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.
  12. Jean-François Trempe

    Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. 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.
    ORCID icon "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.

Reviewing Editor

  1. Ivan Dikic, Goethe University Frankfurt, Germany

Version history

  1. Received: November 8, 2017
  2. Accepted: April 19, 2018
  3. Accepted Manuscript published: April 20, 2018 (version 1)
  4. Version of Record published: April 30, 2018 (version 2)

Copyright

© 2018, McLelland et al.

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.

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  1. Gian-Luca McLelland
  2. Thomas Goiran
  3. Wei Yi
  4. Geneviève Dorval
  5. Carol X Chen
  6. Nadine D Lauinger
  7. Andrea I Krahn
  8. Sepideh Valimehr
  9. Aleksandar Rakovic
  10. Isabelle Rouiller
  11. Thomas M Durcan
  12. Jean-François Trempe
  13. Edward A Fon
(2018)
Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy
eLife 7:e32866.
https://doi.org/10.7554/eLife.32866

Share this article

https://doi.org/10.7554/eLife.32866

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