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
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.
