Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State. Issue 3 (21st March 2019)

• Record Type: Journal Article
• Authors: Magtanong, Leslie; Ko, Pin-Joe; To, Milton; Cao, Jennifer Yinuo; Forcina, Giovanni C.; Tarangelo, Amy; Ward, Carl C.; Cho, Kevin; Patti, Gary J.; Nomura, Daniel K.; Olzmann, James A.; Dixon, Scott J.
• Is Part Of: Cell chemical biology. Volume 26:Issue 3(2019)
• Page Start: 420
• Page End: 432.e9
• Publication Date: 2019-03-21
• Subjects: ferroptosis -- oleate -- MUFAs -- iron -- lipid ROS -- cell death -- lipotoxicity -- GPX4 -- lipid droplet; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.11.016
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state. Graphical Abstract: Highlights: Exogenous MUFAs inhibit ferroptosis in a structure-specific manner MUFAs block lipid ROS accumulation specifically at the plasma membrane Exogenous MUFAs inhibit ferroptosis in an ACSL3-dependent manner Exogenous MUFAs inhibit apoptotic lipotoxicity in an ACSL3-independent manner Abstract : Exogenous lipids can modulate both apoptotic and non-apoptotic cell death. Here we show that exogenous monounsaturated fatty acids can suppress the non-apoptotic process of ferroptosis by promoting the displacement of polyunsaturated fatty acids from plasma membrane phospholipids in an ACSL3-dependent manner.