Iron Catalysis of Lipid Peroxidation in Ferroptosis: Regulated Enzymatic or Random Free Radical Reaction?

Details

• Personal Author:
  Bahar I ; Bayir H ; Bolevich SB ; Jadhav S ; Kagan VE ; Kozlov AV ; Philpott CC ; Protchenko O ; Shrivastava I ; Shvedova AA ; Stoyanovsky DA ; Tyurin VA ; Tyurina YY ; Vladimirov YA
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Ferrous Compounds Lipids Occupational Health Safety
• Keywords:
  15-lipoxygenase Author Keywords: Ferroptosis Biological Effects Cell Death Enzymatic Effects Glutathione GPX4 Hazards Hydroperoxy-arachidonoylphosphatidylethanolamine Iron Iron Chaperons Lipid Peroxidation Metabolism Oxidation Proteins

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• ISSN:
  0891-5849
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; OSHA Region 3 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  153-161
• Volume:
  133
• NIOSHTIC Number:
  nn:20053239
• Citation:
  Free Radic Biol Med 2019 Mar; 133:153-161
• Contact Point Address:
  V.E. Kagana, Center for Free Radical and Antioxidant Heath, Department of Environmental Health, University of Pittsburgh
• Email:
  kagan@pitt.edu
• CAS Registry Number:
  Iron (CAS RN 7439-89-6)
• Federal Fiscal Year:
  2019
• NORA Priority Area:
  Mining
• Peer Reviewed:
  True
• Source Full Name:
  Free Radical Biology and Medicine
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1888c659f8ba50ca11202267385a79e4beb7523cd9c026393eb2d8463171db1c0d2969946961d7919c90542566b4e09dbfff52d53d6e464783e9b4ba248c99d2
• Download URL:
  https://stacks.cdc.gov/view/cdc/216037/cdc_216037_DS1.pdf
• File Type:
  [PDF - 1.87 MB ]