Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis

Tamil S Anthonymuthu; Yulia Y Tyurina; Wan-Yang Sun; Karolina Mikulska-Ruminska; Indira H Shrivastava; Vladimir A Tyurin; Fatma B Cinemre; Haider H Dar; Andrew P VanDemark; Theodore R Holman; Yoel Sadovsky; Brent R Stockwell; Rong-Rong He; Ivet Bahar; Hülya Bayır; Valerian E Kagan

doi:10.1016/j.redox.2020.101744

Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis

Redox Biol. 2021 Jan:38:101744. doi: 10.1016/j.redox.2020.101744. Epub 2020 Oct 16.

Authors

Tamil S Anthonymuthu¹, Yulia Y Tyurina², Wan-Yang Sun³, Karolina Mikulska-Ruminska⁴, Indira H Shrivastava⁵, Vladimir A Tyurin², Fatma B Cinemre⁶, Haider H Dar², Andrew P VanDemark⁷, Theodore R Holman⁸, Yoel Sadovsky⁹, Brent R Stockwell¹⁰, Rong-Rong He¹¹, Ivet Bahar¹², Hülya Bayır¹³, Valerian E Kagan¹⁴

Affiliations

¹ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
² Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
³ Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, College of Pharmacy, Guangzhou, China.
⁴ Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA; Institute of Physics, Faculty of Physics Astronomy and Informatics, Nicolaus Copernicus University in Toruń, Grudziadzka 5, 87-100 Torun, Poland.
⁵ Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Sakarya University School of Medicine, Sakarya, Turkey.
⁷ Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
⁹ Magee-Womens Research Institute and Departments of OBGYN and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA.
¹¹ Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, College of Pharmacy, Guangzhou, China.
¹² Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: bayihx@ccm.upmc.edu.
¹⁴ Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Navigational Redox Lipidomics Group, Institute for Regenerative Medicine, IM Sechenov First Moscow State Medical University, Russian Federation. Electronic address: kagan@pitt.edu.

Abstract

Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) is a ferroptotic cell death signal. HpETE-PE is produced by the 15-Lipoxygenase (15LOX)/Phosphatidylethanolamine Binding Protein-1 (PEBP1) complex or via an Fe-catalyzed non-enzymatic radical reaction. Ferrostatin-1 (Fer-1), a common ferroptosis inhibitor, is a lipophilic radical scavenger but a poor 15LOX inhibitor arguing against 15LOX having a role in ferroptosis. In the current work, we demonstrate that Fer-1 does not affect 15LOX alone, however, it effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows that Fer-1 binds to the 15LOX/PEBP1 complex at three sites and could disrupt the catalytically required allosteric motions of the 15LOX/PEBP1 complex. Using nine ferroptosis cell/tissue models, we show that HpETE-PE is produced by the 15LOX/PEBP1 complex and resolve the long-existing Fer-1 anti-ferroptotic paradox.

Keywords: 15-Lipoxygenase; Ferroptosis; Ferrostatin-1; Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamines; Phospholipid peroxidation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Death
Cyclohexylamines
Ferroptosis*
Oxidation-Reduction
Phenylenediamines

Substances

Cyclohexylamines
Phenylenediamines
ferrostatin-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding