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

Autor: Ganji R; Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Xi Y; Department of Immunobiology, BIO5 Institute, University of Arizona College of Medicine, Tucson, AZ, USA., Kline I; Department of Immunobiology, BIO5 Institute, University of Arizona College of Medicine, Tucson, AZ, USA., Zhu J; Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.; Ilumina Inc., San Diego, CA, USA., Clemen CS; Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany.; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany., Weihl CC; Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA., Purdy JG; Department of Immunobiology, BIO5 Institute, University of Arizona College of Medicine, Tucson, AZ, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Raman M; Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA. malavika.raman@tufts.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Feb 06; Vol. 14 (1), pp. 638. Date of Electronic Publication: 2023 Feb 06.
DOI: 10.1038/s41467-023-36298-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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