A non-canonical vitamin K cycle is a potent ferroptosis suppressor

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Eikan Mishima - , Institute of Metabolism and Cell Death (Autor:in)
  • Junya Ito - , Tohoku Medical and Pharmaceutical University (Autor:in)
  • Zijun Wu - , University of Ottawa (Autor:in)
  • Toshitaka Nakamura - , Institute of Metabolism and Cell Death (Autor:in)
  • Adam Wahida - , Institute of Metabolism and Cell Death (Autor:in)
  • Sebastian Doll - , Institute of Metabolism and Cell Death (Autor:in)
  • Wulf Tonnus - , Medizinische Klinik und Poliklinik 3, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden (Autor:in)
  • Palina Nepachalovich - , Zentrum für Membranbiochemie und Lipidforschung, Fakultät Biologie, Hochschulmedizin (Medizinische Fakultät und Universitätsklinikum), Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universitätsklinikum Leipzig , Medizinische Fakultät Carl Gustav Carus Dresden, Technical University of Sofia (Autor:in)
  • Elke Eggenhofer - , Universitätsklinikum Regensburg (Autor:in)
  • Maceler Aldrovandi - , Institute of Metabolism and Cell Death (Autor:in)
  • Bernhard Henkelmann - , Institute of Metabolism and Cell Death (Autor:in)
  • Ken-Ichi Yamada - , Kyushu University (Autor:in)
  • Jonas Wanninger - , Institute of Metabolism and Cell Death (Autor:in)
  • Omkar Zilka - , University of Ottawa (Autor:in)
  • Emiko Sato - , Tohoku University Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences (Autor:in)
  • Regina Feederle - , Monoclonal Antibody Core Facility (Autor:in)
  • Daniela Hass - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Adriano Maida - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • André Santos Dias Mourão - , Institute of Structural Biology (Autor:in)
  • Andreas Linkermann - , Medizinische Klinik und Poliklinik 3, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden (Autor:in)
  • Edward K Geissler - , Universitätsklinikum Regensburg (Autor:in)
  • Kiyotaka Nakagawa - , Tohoku Medical and Pharmaceutical University (Autor:in)
  • Takaaki Abe - , Tohoku University Graduate School of Medicine (Autor:in)
  • Maria Fedorova - , Zentrum für Membranbiochemie und Lipidforschung, Hochschulmedizin (Medizinische Fakultät und Universitätsklinikum), Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universitätsklinikum Leipzig , Medizinische Fakultät Carl Gustav Carus Dresden, Technical University of Sofia (Autor:in)
  • Bettina Proneth - , Institute of Metabolism and Cell Death (Autor:in)
  • Derek A Pratt - , University of Ottawa (Autor:in)
  • Marcus Conrad - , Institute of Metabolism and Cell Death (Autor:in)

Abstract

Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone3-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.

Details

OriginalspracheEnglisch
Seiten (von - bis)778-783
Seitenumfang6
FachzeitschriftNature
Jahrgang608
Ausgabenummer7924
PublikationsstatusVeröffentlicht - Aug. 2022
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC9402432
Scopus 85135300913
ORCID /0000-0001-6287-9725/work/145698877
ORCID /0000-0002-9728-1413/work/145699149
ORCID /0000-0002-4692-3885/work/148143334

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Antidotes/pharmacology, Antioxidants/metabolism, Carbon-Carbon Ligases/metabolism, Coenzymes/metabolism, Ferroptosis/drug effects, Hydroquinones/metabolism, Lipid Peroxidation/drug effects, Oxidation-Reduction, S100 Calcium-Binding Protein A4/metabolism, Vitamin K/metabolism, Warfarin/adverse effects