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

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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.

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0003-2314-7147
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.

"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.

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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.