Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism

  1. Agustin Leonardo Lujan
  2. Ombretta Foresti
  3. Conor Sugden
  4. Nathalie Brouwers
  5. Alex Mateo Farre
  6. Alessio Vignoli
  7. Mahshid Azamian
  8. Alicia Turner
  9. Jose Wojnacki
  10. Vivek Malhotra  Is a corresponding author
  1. Barcelona Institute for Science and Technology, Spain
  2. Baylor College of Medicine, United States

Abstract

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen (ROS), and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.

Data availability

"TANGO2 - Source data files" (https://doi.org/10.5061/dryad.rn8pk0pg5) to Dryad.

The following data sets were generated
    1. Lujan AL
    (2023) TANGO2 - Source data files
    Dryad Digital Repository, doi:10.5061/dryad.rn8pk0pg5.

Article and author information

Author details

  1. Agustin Leonardo Lujan

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4906-6951
  2. Ombretta Foresti

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6878-0395
  3. Conor Sugden

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
  4. Nathalie Brouwers

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9808-9394
  5. Alex Mateo Farre

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
  6. Alessio Vignoli

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7131-2915
  7. Mahshid Azamian

    Center for Cell and Gene Therapy, Baylor College of Medicine, Texas, United States
    Competing interests
    No competing interests declared.
  8. Alicia Turner

    Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, United States
    Competing interests
    No competing interests declared.
  9. Jose Wojnacki

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
  10. Vivek Malhotra

    Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
    For correspondence
    vivek.malhotra@crg.eu
    Competing interests
    Vivek Malhotra, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6198-7943

Funding

Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (PID2019-105518GB-I00)

  • Agustin Leonardo Lujan

European Research Council (ERC-2020-SyG-Proposal No. 951146)

  • Agustin Leonardo Lujan
  • Ombretta Foresti
  • Conor Sugden
  • Nathalie Brouwers
  • Alex Mateo Farre
  • Alessio Vignoli
  • Jose Wojnacki
  • Vivek Malhotra

European Molecular Biology Organization (EMBO ALTF 659-2021)

  • Agustin Leonardo Lujan

European Research Council (H2020-MSCA-IF-2019-894115)

  • Jose Wojnacki

Ministerio de Ciencia e Innovación (RYC-2016-20919)

  • Ombretta Foresti

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

Copyright

© 2023, Lujan 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. Agustin Leonardo Lujan
  2. Ombretta Foresti
  3. Conor Sugden
  4. Nathalie Brouwers
  5. Alex Mateo Farre
  6. Alessio Vignoli
  7. Mahshid Azamian
  8. Alicia Turner
  9. Jose Wojnacki
  10. Vivek Malhotra
(2023)
Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism
eLife 12:e85345.
https://doi.org/10.7554/eLife.85345

Share this article

https://doi.org/10.7554/eLife.85345

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