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

doi:10.1016/j.celrep.2023.113023

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

Cell Rep. 2023 Sep 26;42(9):113023. doi: 10.1016/j.celrep.2023.113023. Epub 2023 Sep 8.

Authors

Vaishnavi V Phadnis¹, Jamie Snider², Venkateshwari Varadharajan³, Iyappan Ramachandiran³, Amy A Deik⁴, Zon Weng Lai⁵, Tenzin Kunchok⁶, Elinor Ng Eaton⁶, Carolin Sebastiany⁶, Anna Lyakisheva², Kyle D Vaccaro⁶, Juliet Allen⁶, Zhong Yao², Victoria Wong², Betty Geng², Kipp Weiskopf⁷, Clary B Clish⁴, J Mark Brown³, Igor Stagljar⁸, Robert A Weinberg⁹, Whitney S Henry¹⁰

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA.
² Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
³ 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.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
⁶ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁷ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ 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.
⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA. Electronic address: weinberg@wi.mit.edu.
¹⁰ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: whenry@wi.mit.edu.

Abstract

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.

Keywords: ACSL4; CP: Cell biology; MBOAT7; MMD; arachidonic acid; cancer; ferroptosis; lipid metabolism; phosphatidylinositol; polyunsaturated fatty acid; scaffold.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Line
Fatty Acids, Unsaturated
Ferroptosis*
Humans
Phosphatidylinositols* / metabolism
Phospholipids / metabolism

Substances

Fatty Acids, Unsaturated
Phosphatidylinositols
Phospholipids
MMD protein, human
long-chain-fatty-acid-CoA ligase
MBOAT7 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding