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The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition

Author

Listed:
  • Rakesh Ganji

    (Tufts University School of Medicine)

  • Joao A. Paulo

    (Harvard Medical School)

  • Yuecheng Xi

    (University of Arizona College of Medicine)

  • Ian Kline

    (University of Arizona College of Medicine)

  • Jiang Zhu

    (Washington University School of Medicine
    Ilumina Inc.)

  • Christoph S. Clemen

    (German Aerospace Center
    University of Cologne)

  • Conrad C. Weihl

    (Washington University School of Medicine)

  • John G. Purdy

    (University of Arizona College of Medicine)

  • Steve P. Gygi

    (Harvard Medical School)

  • Malavika Raman

    (Tufts University School of Medicine)

Abstract

The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.

Suggested Citation

  • Rakesh Ganji & Joao A. Paulo & Yuecheng Xi & Ian Kline & Jiang Zhu & Christoph S. Clemen & Conrad C. Weihl & John G. Purdy & Steve P. Gygi & Malavika Raman, 2023. "The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36298-2
    DOI: 10.1038/s41467-023-36298-2
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    References listed on IDEAS

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    1. Rebecca Bertolio & Francesco Napoletano & Miguel Mano & Sebastian Maurer-Stroh & Marco Fantuz & Alessandro Zannini & Silvio Bicciato & Giovanni Sorrentino & Giannino Del Sal, 2019. "Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Radu Stoica & Kurt J. De Vos & Sébastien Paillusson & Sarah Mueller & Rosa M. Sancho & Kwok-Fai Lau & Gema Vizcay-Barrena & Wen-Lang Lin & Ya-Fei Xu & Jada Lewis & Dennis W. Dickson & Leonard Petrucel, 2014. "ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43," Nature Communications, Nature, vol. 5(1), pages 1-12, September.
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    1. Ying Zhu & Kerem Can Akkaya & Julia Ruta & Nanako Yokoyama & Cong Wang & Max Ruwolt & Diogo Borges Lima & Martin Lehmann & Fan Liu, 2024. "Cross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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