MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis

Vaishnavi V. Phadnis; Jamie Snider; Venkateshwari Varadharajan; Iyappan Ramachandiran; Amy A. Deik; Zon Weng Lai; Tenzin Kunchok; Elinor Ng Eaton; Carolin Sebastiany; Anna Lyakisheva; Kyle D. Vaccaro; Juliet Allen; Zhong Yao; Victoria Wong; Betty Geng; Kipp Weiskopf; Clary B. Clish; J. Mark Brown; Igor Stagljar; Robert A. Weinberg; Whitney S. Henry

Cell Reports (Sep 2023)

MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis

Vaishnavi V. Phadnis,
Jamie Snider,
Venkateshwari Varadharajan,
Iyappan Ramachandiran,
Amy A. Deik,
Zon Weng Lai,
Tenzin Kunchok,
Elinor Ng Eaton,
Carolin Sebastiany,
Anna Lyakisheva,
Kyle D. Vaccaro,
Juliet Allen,
Zhong Yao,
Victoria Wong,
Betty Geng,
Kipp Weiskopf,
Clary B. Clish,
J. Mark Brown,
Igor Stagljar,
Robert A. Weinberg,
Whitney S. Henry

Affiliations

Vaishnavi V. Phadnis: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA
Jamie Snider: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Venkateshwari Varadharajan: Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Iyappan Ramachandiran: Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Amy A. Deik: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Zon Weng Lai: Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
Tenzin Kunchok: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Elinor Ng Eaton: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Carolin Sebastiany: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Anna Lyakisheva: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Kyle D. Vaccaro: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Juliet Allen: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Zhong Yao: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Victoria Wong: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Betty Geng: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Kipp Weiskopf: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA
Clary B. Clish: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
J. Mark Brown: Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Igor Stagljar: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Mediterranean Institute for Life Sciences, 21000 Split, Croatia
Robert A. Weinberg: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Corresponding author
Whitney S. Henry: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113023

Abstract

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Summary: Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.

CP: Cell biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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