Details

Autor(en) / Beteiligte

• Stoyanovsky, D.A.
• Tyurina, Y.Y.
• Shrivastava, I.
• Bahar, I.
• Tyurin, V.A.
• Protchenko, O.
• Jadhav, S.
• Bolevich, S.B.
• Kozlov, A.V.
• Vladimirov, Y.A.
• Shvedova, A.A.
• Philpott, C.C.
• Bayir, H.
• Kagan, V.E.

Titel

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

Ist Teil von

• Free radical biology & medicine, 2019-03, Vol.133, p.153-161

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Phospholipid peroxidation in ferroptosis.•Lipoxygenase oxidation of arachidonoyl phosphatidylethanolamine.•Guided transportation of iron to target destinations in cells.•GPX4 reduction of hydroperoxy-arachidonoyl-phosphatidylethanolamine.•ACSL4 biosynthesis of arachidonoyl phosphatidylethanolamine is required for.