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

Ganji, Rakesh and Paulo, Joao A. and Xi, Yuecheng and Kline, Ian and Zhu, Jiang and Clemen, Christoph S. and Weihl, Conrad C. and Purdy, John G. and Gygi, Steve P. and Raman, Malavika (2023) The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, 14 (1), p. 638. Nature Publishing Group. doi: 10.1038/s41467-023-36298-2. ISSN 2041-1723.

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Official URL: https://dx.doi.org/10.1038/s41467-023-36298-2

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

Item URL in elib:https://elib.dlr.de/195100/
Document Type:Article
Title:The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iDORCID Put Code
Ganji, RakeshTufts University School of Medicine, Department of Developmental Molecular and Chemical Biology, Boston, MA, USAhttps://orcid.org/0000-0003-2874-5007UNSPECIFIED
Paulo, Joao A.Harvard Medical School, Department of Cell Biology, Boston, MA, USAhttps://orcid.org/0000-0002-4291-413XUNSPECIFIED
Xi, YuechengUniversity of Arizona College of Medicine, Department of Immunobiology, BIO5 Institute, Tucson, AZ, USAUNSPECIFIEDUNSPECIFIED
Kline, IanUniversity of Arizona College of Medicine, Department of Immunobiology, BIO5 Institute, Tucson, AZ, USAUNSPECIFIEDUNSPECIFIED
Zhu, JiangWashington University School of Medicine, Department of Neurology,Saint Louis, MO, USAUNSPECIFIEDUNSPECIFIED
Clemen, Christoph S.German Aerospace Center (DLR), Institute of Aerospace Medicine, Gravitational Biology, Colognehttps://orcid.org/0000-0002-1291-4219UNSPECIFIED
Weihl, Conrad C.Washington University School of Medicine, Department of Neurology,Saint Louis, MO, USAUNSPECIFIEDUNSPECIFIED
Purdy, John G.University of Arizona College of Medicine, Department of Immunobiology, BIO5 Institute, Tucson, AZ, USAhttps://orcid.org/0000-0001-7460-7567UNSPECIFIED
Gygi, Steve P.Harvard Medical School, Department of Cell Biology, Boston, MA, USAhttps://orcid.org/0000-0001-7626-0034UNSPECIFIED
Raman, MalavikaTufts University School of Medicine, Department of Developmental Molecular and Chemical Biology, Boston, MA, USAhttps://orcid.org/0000-0002-4773-8673UNSPECIFIED
Date:6 February 2023
Journal or Publication Title:Nature Communications
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:14
DOI:10.1038/s41467-023-36298-2
Page Range:p. 638
Publisher:Nature Publishing Group
ISSN:2041-1723
Status:Published
Keywords:Neurodegeneration, p97-UBXD8, ER-Mitochondria, membrane lipid, mice, mutations
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - NeuroSpace
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Gravitational Biology
Deposited By: Chiodo, Annette
Deposited On:23 May 2023 12:48
Last Modified:24 May 2023 13:23

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