Cell Programs for Elimination of the Unnecessary: Fatal Role of Peroxidized Lipids

Abstract:

Amphiphilc polyunsaturated lipids are essential for life as structural building blocks of biological membranes and as signaling molecules. Coordination of numerous metabolic reactions and pathways requires high diversification of lipids which is achieved, to a large extent, via oxygenation of polyunsaturated lipids. This fundamental role of oxygenated polyunsaturated lipids in regulation is associated with a risk of their injurious effects via aberrant reactions of hydrophobic electrophilic carbonyl compounds – aldehydes, ketones, epoxides – with essential nucleophilic sites in proteins. These secondary reactive lipid electrophiles are generated from the common hydroperoxy-precursors, the primary molecular products of lipid peroxidation reactions. Therefore, control of the hydroperoxy-lipids is operated by the key intracellular redox regulatory system – thiols and their discoordination may lead to different types of regulated cell death as exemplified by apoptosis and ferroptosis. In apoptosis, formation of a complex between an intermembrane space hemoprotein, cytochrome c (cyt c), and a mitochondrial-specific phospholipid, cardiolipin, results in the peroxidation of the latter leading to the release of cyt c into the cytosol and subsequent pro-apoptotic reactions. In ferroptosis, a newly identified iron dependent form of regulated cell death, hydroperoxy-phosphatidylethanolamines generated by 15-lipoxygenases have been identified as the proximate ferroptotic death signals in cells. The ferroptotic pathway is an evolutionarily conserved pathway employed by bacterial pathogens as a theft-ferroptotic mechanism hijacking the host phospholipids to generate HOO-AA-PE death signals in epithelial cells.