Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction?

Abstract

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.

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

“…Iron not only directly catalyzes the formation of ROS, but also synthesizes the LOXs that oxidize PUFAs to result in lipid peroxides in ferroptosis. Altogether, iron is the essential component of ferroptosis (Stoyanovsky et al, 2019).…”

Male Infertility: Shining a Light on Lipids and Lipid-Modulating Enzymes in the Male Germline

“…The ferroptotic pathway is initiated by the inactivation of the glutathione peroxidase 4 (GPX4), an antioxidant enzyme that affords membrane protection via the active reduction of lipid hydroperoxides [50]. It follows that GPX4 inactivation and/or depletion of its substrate glutathione (GSH) enables the accumulation of lipid hydroperoxides, the production of which is catalyzed by enzymes, such as lipoxygenases [51]. Recently, an alternative defense system based on the activity of ferroptosis-suppressor-protein 1 (FSP1) has been reported, which offers additional protection against lipid peroxidation and the ferroptosis cascade, even after GPX4 ablation [52].…”

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

“…Iron is fundamental to the production of reactive oxygen species (ROS); hydroxyl radicals are formed by the Fenton reaction [174]. When excessive, ROS causes mitochondrial dysfunction, DNA destruction [175], lipid peroxidation [175,176], and the iron-based cell death process ferroptosis [177,178]. ROS levels can be modulated by a number of factors, including SOD, catalase, glutathione peroxidase, glutathione, cysteine, ascorbic acid, and alpha-tocopherol (vitamin E) [179,180].…”