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Mishima, E. ; Ito, J.* ; Wu, Z.* ; Nakamura, T. ; Wahida, A. ; Doll, S. ; Tonnus, W.* ; Nepachalovich, P.* ; Eggenhofer, E.* ; Aldrovandi, M. ; Henkelmann, B. ; Yamada, K.i.* ; Wanninger, J. ; Zilka, O.* ; Sato, E.* ; Feederle, R. ; Hass, D, ; Maida, A. ; Mourao, A. ; Linkermann, A.* ; Geissler, E.K.* ; Nakagawa, K.* ; Abe, T.* ; Fedorova, M.* ; Proneth, B. ; Pratt, D.A.* ; Conrad, M.

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

Nature 608, 778-783 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 608, Heft: 7924, Seiten: 778-783 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
CF Monoclonal Antibodies (CF-MAB)
Institute of Diabetes and Cancer (IDC)
Institute of Structural Biology (STB)
Förderungen European Research Council