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
Affiliations
Tamil S. Anthonymuthu
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
Yulia Y. Tyurina
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
Wan-Yang Sun
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
Karolina Mikulska-Ruminska
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
Indira H. Shrivastava
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
Vladimir A. Tyurin
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
Fatma B. Cinemre
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
Haider H. Dar
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
Andrew P. VanDemark
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
Theodore R. Holman
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA
Yoel Sadovsky
Magee-Womens Research Institute and Departments of OBGYN and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
Brent R. Stockwell
Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
Rong-Rong He
Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, College of Pharmacy, Guangzhou, China
Ivet Bahar
Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA
Hülya Bayır
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; Corresponding author. Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
Valerian E. Kagan
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; Corresponding author. Room 4120, 130 De Soto Street, Pittsburgh, PA, 15219, USA.
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.
