An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

  1. Tricia T Nguyen
  2. Gia K Voeltz  Is a corresponding author
  1. University of Colorado Boulder, United States

Abstract

Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, ABHD16A, as a major regulator of node formation. In the absence of ABHD16A, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes and fission and fusion rates are significantly reduced. ABHD16A contains an acyltransferase motif and an α/β hydrolase domain and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby ABHD16A functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source Data files have been provided for Figures 1-7 and supplementary Figures 1, 2, 4, 5, and 6. Source data contains numerical data or either uncropped western blots used to generate the figures.

Article and author information

Author details

  1. Tricia T Nguyen

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2314-7147
  2. Gia K Voeltz

    Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
    For correspondence
    gia.voeltz@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3199-5402

Funding

National Institutes of Health (T32 Training Grants GM008759 and GM142607)

  • Tricia T Nguyen

National Institutes of Health (GM120998)

  • Gia K Voeltz

Howard Hughes Medical Institute

  • Gia K Voeltz

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

Reviewing Editor

  1. Randy Schekman, Howard Hughes Medical Institute, University of California, Berkeley, United States

Version history

  1. Received: October 18, 2022
  2. Preprint posted: October 24, 2022 (view preprint)
  3. Accepted: November 29, 2022
  4. Accepted Manuscript published: November 30, 2022 (version 1)
  5. Version of Record published: December 6, 2022 (version 2)

Copyright

© 2022, Nguyen & Voeltz

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. Tricia T Nguyen
  2. Gia K Voeltz
(2022)
An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion
eLife 11:e84279.
https://doi.org/10.7554/eLife.84279

Share this article

https://doi.org/10.7554/eLife.84279

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