Abstract
Phospholipids were essential for life from the very early stages of it emerence. With the appearance of molecular oxygen and multicellularity - polyunsaturated lipids played two important roles: 1) as structural building blocks of membranes, and 2) as communication signals. Among many different mechanisms, oxygenation of polyunsaturated lipids played an essential role in coordinating numerous metabolic reactions and pathways. This paramount role of oxygenated polyunsaturated lipids in regulation is also associated with a risk of their involvement in aberrant injury reactions due to lipid peroxidation and the production of secondary reactive lipid electrophiles. Discoordination of these oxygenation reactions leads to ferroptosis, a non-apoptotic, iron dependent form of regulated cell death. We will present new data identifying hydroperoxy-phosphatidylethanolamines generated by 15-lipoxygenases (15LO). We found that 15LO oxygenate free polyunsaturated fatty acids (PUFA) but can change their substrate specificity to generate hydroperoxy-PUFA phosphatidyl-ethanolamines (PUFAPEs) which - under conditions of GPX4 deficiency - trigger ferroptosis. We sought a common pro-ferroptotic regulator for 15LO using oxidative phospholipidomics, confocal-based immunolocalization techniques, redox biochemistry and computational biology. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate pro-ferroptotic hydroperoxy-PUFA-PE.
Published Version
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