@article{1c426a94225d49a382440c438e009b1c,
title = "The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition",
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.",
author = "Rakesh Ganji and Paulo, {Joao A.} and Yuecheng Xi and Ian Kline and Jiang Zhu and Clemen, {Christoph S.} and Weihl, {Conrad C.} and Purdy, {John G.} and Gygi, {Steve P.} and Malavika Raman",
note = "Funding Information: We thank Peter Juo and Karl Munger for critical reading of the manuscript. We are grateful to Jeffrey Golden (Brigham and Women{\textquoteright}s Hospital, Harvard Medical School) for split luciferase constructs, and the Whitehead Institute Electron Microscopy core for electron microscopy. We are grateful to Christopher Miller (King{\textquoteright}s College London) for VAPB and PTPIP51 constructs. We are grateful to Marisa Brini and Tito Cali (University of Padova, Italy) for SPLICS constructs. We would also like to thank Jacob Klickstein for developing the ImageJ script for ER–mitochondria co-localization. We thank Brittany Ahlstedt for performing ER stress measurements in wildtype and UBXD8 KO cells. This work is supported by the NIH grant GM127557 to M.R., funds from the University of Arizona Health Sciences, BIO5 Institute and NIH grant AI162671 to J.G.P., NIH grant T32 AG058503 to I.K., and NIH grant AG031867 to C.C.W. Funding Information: The mass spectrometry proteomics data related to Fig. and Supplementary Fig. have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD039061 . All raw lipidomic data are available in supplementary Dataset . The mass spectrometry lipidomics data is available at the NIH Common Fund{\textquoteright}s National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, ( https://www.metabolomicsworkbench.org ), where it has been assigned Project ID PR001559 [ https://doi.org/10.21228/M85X3W ] with StudyIDs ST002421 (for whole-cell lipidomics) and ST002422 (MAM fraction lipidomics). This work is supported by NIH grant, U2C- DK119886. Any other data are available from the corresponding author upon request. are provided with this paper. Funding Information: We thank Peter Juo and Karl Munger for critical reading of the manuscript. We are grateful to Jeffrey Golden (Brigham and Women{\textquoteright}s Hospital, Harvard Medical School) for split luciferase constructs, and the Whitehead Institute Electron Microscopy core for electron microscopy. We are grateful to Christopher Miller (King{\textquoteright}s College London) for VAPB and PTPIP51 constructs. We are grateful to Marisa Brini and Tito Cali (University of Padova, Italy) for SPLICS constructs. We would also like to thank Jacob Klickstein for developing the ImageJ script for ER–mitochondria co-localization. We thank Brittany Ahlstedt for performing ER stress measurements in wildtype and UBXD8 KO cells. This work is supported by the NIH grant GM127557 to M.R., funds from the University of Arizona Health Sciences, BIO5 Institute and NIH grant AI162671 to J.G.P., NIH grant T32 AG058503 to I.K., and NIH grant AG031867 to C.C.W. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-36298-2",
language = "English",
volume = "14",
journal = "Nature communications",
issn = "2041-1723",
number = "1",
}