IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36298-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36298-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36298-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Tiago C. Silva & Juan I. Young & Lanyu Zhang & Lissette Gomez & Michael A. Schmidt & Achintya Varma & X. Steven Chen & Eden R. Martin & Lily Wang, 2022. "Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Zhiren Wang & Wenpan Li & Yanhao Jiang & Jonghan Park & Karina Marie Gonzalez & Xiangmeng Wu & Qing-Yu Zhang & Jianqin Lu, 2024. "Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Hyunwoo Kim & Seowhang Lee & Youngsoo Jun & Changwook Lee, 2022. "Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Eunbyul Cho & Youngsik Woo & Yeongjun Suh & Bo Kyoung Suh & Soo Jeong Kim & Truong Thi My Nhung & Jin Yeong Yoo & Tran Diem Nghi & Su Been Lee & Dong Jin Mun & Sang Ki Park, 2023. "Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36298-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.