Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamine binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their "protein clients" thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of pro-ferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by combining its catalytic role in the 15-LOX-driven production of 15-hydroperoxy-AA-PE (HOO-AA-PE) as well as possible involvement of loosely-bound iron in oxidative cleavage of HOO-AA-PE to oxidatively truncated electrophiles capable of attacking nucleophilic targets in yet to be identified proteins leading to cell demise.

Aerobic life is based on numerous metabolic oxidation reactions as well as biosynthesis of oxygenated signaling compounds. Among the latter are the myriads of oxygenated lipids including a well-studied group of polyunsaturated fatty acids (PUFA) - octadecanoids, eicosanoids, and docosanoids. During the last two decades, remarkable progress in liquid-chromatography-mass spectrometry has led to significant progress in the characterization of oxygenated PUFA-containing phospholipids, thus designating the emergence of a new field of lipidomics, redox lipidomics. Although non-enzymatic free radical reactions of lipid peroxidation have been mostly associated with the aberrant metabolism typical of acute injury or chronic degenerative processes, newly accumulated evidence suggests that enzymatically catalyzed (phospho)lipid oxygenation reactions are essential mechanisms of many physiological pathways. In this review, we discuss a variety of contemporary protocols applicable for identification and quantitative characterization of different classes of peroxidized (phospho)lipids. We describe applications of different types of LC-MS for analysis of peroxidized (phospho)lipids, particularly cardiolipins and phosphatidylethanolalmines, in two important types of programmed cell death - apoptosis and ferroptosis. We discuss the role of peroxidized phosphatidylserines in phagocytotic signaling. We exemplify the participation of peroxidized neutral lipids, particularly tri-acylglycerides, in immuno-suppressive signaling in cancer. We also consider new approaches to exploring the spatial distribution of phospholipids in the context of their oxidizability by MS imaging, including the latest achievements in high resolution imaging techniques. We present innovative approaches to interpretation of LC-MS data, including their audio-representation analysis. Overall, we emphasize the role of redox lipidomics as a communication language, unprecedented in diversity and richness, through the analysis of peroxidized (phospho)lipids.

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