Oxidation Of Phosphatidylethanolamine Research Articles

Oxidation of phosphatidylethanolamines as ferroptotic signals: control by lipoxygenases

Since the emergence of life on our planet, phospholipids played a very essential role by fulfilling two major functions as: 1) structural components of membranes, and 2) as signaling molecules. The latter is mostly associated with oxygenation of polyunsaturated (phospho)lipids. In this talk, I will focus on the role, mechanisms and regulation of phospholipid oxidation in ferroptosis, the latest addition to the list of regulated cell death pathways. The data will be presented linking ferroptosis with catalytic activity of 15-lipoxygenases and their allosteric regulation by a scaffold-protein, PEBP1, resulting in the generation of 15-hydro-peroxy-arachidonoyl(adrenoyl)-phosphatidylethanolamines. Examples illustrating the contribution of ferroptosis in vivo will be presented such as asthma exacerbations, acute renal injury and traumatic brain injury. Potential role of bacterial lipoxygenases will be considered in lieu of their propensity to oxidize membrane phospholipids.

Oxidation Of Phosphatidylethanolamines As Ferroptotic Signals: Control By Lipoxygenases

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.