MMD Collaborates with ACSL4 and MBOAT7 to Promote Polyunsaturated Phosphatidylinositol Remodeling and Susceptibility to Ferroptosis

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Sep 10

PMID 37691145

Authors

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

Soon will be listed here.

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.

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