MMD scaffolds ACSL4 and MBOAT7 to promote polyunsaturated phospholipid synthesis and susceptibility to ferroptosis

Abstract

Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Ferroptosis is driven by excessive iron-dependent peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid. Here, we reveal that an understudied Golgi membrane scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells. Upregulation of MMD correlates with sensitization to ferroptosis upon monocyte-to-macrophage differentiation. Mechanistically, MMD interacts with ACSL4 and MBOAT7, two enzymes that catalyze consecutive reactions in the biosynthesis of phosphatidylinositol (PI) containing arachidonic acid. MMD increases cellular levels of arachidonoyl-phospholipids and heightens susceptibility to ferroptosis in an ACSL4- and MBOAT7-dependent manner. We propose that MMD potentiates the synthesis of arachidonoyl-PI by bridging ACSL4 with MBOAT7. This molecular mechanism not only clarifies the biochemical underpinnings of ferroptosis susceptibility, with potential therapeutic implications, but also contributes to our understanding of the regulation of cellular lipid metabolism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/506096v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1e5c469org.highwire.dtl.DTLVardef@1c1ec52org.highwire.dtl.DTLVardef@820cceorg.highwire.dtl.DTLVardef@16ca7e_HPS_FORMAT_FIGEXP M_FIG C_FIG