Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State

Magtanong L, KO PJ, To M, Cao JY, Forcina GC, Tarangelo A, Ward CC, Cho K, Patti GJ, Nomura DK, Olzmann JA, Dixon SJ
Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State
Cell Chemical Biology, 26, 1-13, 2019

The initiation and execution of cell death can beregulated by various lipids. How the levels of environ-mental (exogenous) lipids impact cell death sensi-tivity is not well understood. We find that exogenousmonounsaturated fatty acids (MUFAs) potentlyinhibit the non-apoptotic, iron-dependent, oxidativecell death process of ferroptosis. This protectiveeffect is associated with the suppression of lipidreactive oxygen species (ROS) accumulation at theplasma membrane and decreased levels of phospho-lipids containing oxidizable polyunsaturated fattyacids. Treatment with exogenous MUFAs reducesthe sensitivity of plasma membrane lipids to oxida-tion over several hours. This effect requires MUFAactivationbyacyl-coenzyme Asynthetaselong-chainfamily member 3 (ACSL3) and is independent of lipiddroplet formation. Exogenous MUFAs also protectcells from apoptotic lipotoxicity caused by the accu-mulation of saturated fatty acids, but in an ACSL3-in-dependent manner. Our work demonstrates thatACSL3-dependent MUFA activation promotes a fer-roptosis-resistant cell state.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA