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 Deik, Zon Weng Lai, Tenzin Kunchok, Elinor Ng Eaton, Carolin Sebastiany, Anna Lyakisheva, Kyle Vaccaro, Juliet Allen, Zhong Yao, Victoria Wong, Betty Geng, Kipp Weiskopf, Clary B. Clish, J. Mark Brown, Igor Štagljar, Robert A. Weinberg, Whitney S. Henry
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.