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.

CircFOXO3 Upregulation Mediates the Radioresistance of Glioblastoma by Affecting Cellular Metabolome

“…Blood test results after radiation therapy in cancer patients show low levels of the antioxidant glutathione (GSH), and TCGA genome-wide metabolic models show increased synthesis of the antioxidant NADPH in radio-resistant tumors 20 . Radiotherapy can promote lipid peroxidation by producing a large number of ROS and up-regulating the expression of the key enzyme ACSL4, which ultimately leads to iron death in tumor cells 21 . Hence, inhibition of antioxidant pathways has been shown to enhance the anti-cancer effect of radiotherapy in preclinical models.…”

A tale of two lipids: Lipid unsaturation commands ferroptosis sensitivity

“…The contributions of ACSL4 and LPCAT3 to ferroptosis have been extensively reviewed elsewhere [82][83][84][85]. ACSL4 may specifically scaffold with MBOAT7, a Lands cycle enzyme that acylates lysophosphatidylinositol with arachidonoyl-CoA to form PI-PUFAs [76,86,87].…”

“…CRISPR-mediated disruption of MBOAT7 in OVCAR-7 cells reduces their sensitivity to the direct GPX4 inhibitors ML210 and FIN56, indicating that MBOAT7 promotes ferroptosis sensitivity by inserting AA into PI phospholipids [86]. The activity of ACSL4 during ferroptosis may not be passive but in fact highly regulated [88].…”

“…The contributions of ACSL4 and LPCAT3 to ferroptosis have been extensively reviewed elsewhere [82–85]. ACSL4 may specifically scaffold with MBOAT7, a Lands cycle enzyme that acylates lysophosphatidylinositol with arachidonoyl‐CoA to form PI‐PUFAs [76, 86, 87]. CRISPR‐mediated disruption of MBOAT7 in OVCAR‐7 cells reduces their sensitivity to the direct GPX4 inhibitors ML210 and FIN56, indicating that MBOAT7 promotes ferroptosis sensitivity by inserting AA into PI phospholipids [86].…”

“…ACSL4 may specifically scaffold with MBOAT7, a Lands cycle enzyme that acylates lysophosphatidylinositol with arachidonoyl‐CoA to form PI‐PUFAs [76, 86, 87]. CRISPR‐mediated disruption of MBOAT7 in OVCAR‐7 cells reduces their sensitivity to the direct GPX4 inhibitors ML210 and FIN56, indicating that MBOAT7 promotes ferroptosis sensitivity by inserting AA into PI phospholipids [86]. The activity of ACSL4 during ferroptosis may not be passive but in fact highly regulated [88].…”