Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity

Abstract

The human AdipoR1 and AdipoR2 proteins, as well as their C. elegans homolog PAQR-2, protect against cell membrane rigidification by exogenous saturated fatty acids by regulating phospholipid composition. Here, we show that mutations in the C. elegans gene acs-13 help to suppress the phenotypes of paqr-2 mutant worms, including their characteristic membrane fluidity defects. acs-13 encodes a homolog of the human acyl-CoA synthetase ACSL1, and localizes to the mitochondrial membrane where it likely activates long chains fatty acids for import and degradation. Using siRNA combined with lipidomics and membrane fluidity assays (FRAP and Laurdan dye staining) we further show that the human ACSL1 potentiates lipotoxicity by the saturated fatty acid palmitate: silencing ACSL1 protects against the membrane rigidifying effects of palmitate and acts as a suppressor of AdipoR2 knockdown, thus echoing the C. elegans findings. We conclude that acs-13 mutations in C. elegans and ACSL1 knockdown in human cells prevent lipotoxicity by promoting increased levels of polyunsaturated fatty acid-containing phospholipids.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. The lipidomics data is provided as a supplementary table.

Article and author information

Author details

  1. Mario Ruiz

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
  2. Rakesh Bodhicharla

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
  3. Marcus Ståhlman

    Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4202-0339
  4. Emma Svensk

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
  5. Kiran Busayavalasa

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
  6. Henrik Palmgren

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    Henrik Palmgren, affiliated with AstraZeneca. The author has no competing interests to declare. The other authors declare that no competing interests exist..
  7. Hanna Ruhanen

    Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  8. Jan Boren

    Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    No competing interests declared.
  9. Marc Pilon

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    For correspondence
    marc.pilon@cmb.gu.se
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3919-2882

Funding

Vetenskapsrådet (Dnr: 2016-03676)

  • Marc Pilon

Cancerfonden (Dnr 16 0693)

  • Marc Pilon

Carl Tryggers Stiftelse för Vetenskaplig Forskning (CTS 16:365)

  • Marc Pilon

Diabetesfonden (DIA2016-109)

  • Marc Pilon

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

Reviewing Editor

  1. Tobias C Walther, Howard Hughes Medical Institute, University of California, San Francisco, United States

Version history

  1. Received: April 16, 2019
  2. Accepted: November 23, 2019
  3. Accepted Manuscript published: November 26, 2019 (version 1)
  4. Version of Record published: December 9, 2019 (version 2)

Copyright

© 2019, Ruiz 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. Mario Ruiz
  2. Rakesh Bodhicharla
  3. Marcus Ståhlman
  4. Emma Svensk
  5. Kiran Busayavalasa
  6. Henrik Palmgren
  7. Hanna Ruhanen
  8. Jan Boren
  9. Marc Pilon
(2019)
Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity
eLife 8:e47733.
https://doi.org/10.7554/eLife.47733

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https://doi.org/10.7554/eLife.47733

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