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

Eikan Mishima (), Junya Ito, Zijun Wu, Toshitaka Nakamura, Adam Wahida, Sebastian Doll, Wulf Tonnus, Palina Nepachalovich, Elke Eggenhofer, Maceler Aldrovandi, Bernhard Henkelmann, Ken-ichi Yamada, Jonas Wanninger, Omkar Zilka, Emiko Sato, Regina Feederle, Daniela Hass, Adriano Maida, André Santos Dias Mourão, Andreas Linkermann, Edward K. Geissler, Kiyotaka Nakagawa, Takaaki Abe, Maria Fedorova, Bettina Proneth, Derek A. Pratt and Marcus Conrad ()
Additional contact information
Eikan Mishima: Helmholtz Zentrum München
Junya Ito: Tohoku University
Zijun Wu: University of Ottawa
Toshitaka Nakamura: Helmholtz Zentrum München
Adam Wahida: Helmholtz Zentrum München
Sebastian Doll: Helmholtz Zentrum München
Wulf Tonnus: Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden
Palina Nepachalovich: Leipzig University
Elke Eggenhofer: University Hospital Regensburg, University of Regensburg
Maceler Aldrovandi: Helmholtz Zentrum München
Bernhard Henkelmann: Helmholtz Zentrum München
Ken-ichi Yamada: Kyushu University
Jonas Wanninger: Helmholtz Zentrum München
Omkar Zilka: University of Ottawa
Emiko Sato: Tohoku University Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences
Regina Feederle: Helmholtz Zentrum München
Daniela Hass: Helmholtz Zentrum München
Adriano Maida: Helmholtz Zentrum München
André Santos Dias Mourão: Helmholtz Zentrum München
Andreas Linkermann: Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden
Edward K. Geissler: University Hospital Regensburg, University of Regensburg
Kiyotaka Nakagawa: Tohoku University
Takaaki Abe: Tohoku University Graduate School of Medicine
Maria Fedorova: Leipzig University
Bettina Proneth: Helmholtz Zentrum München
Derek A. Pratt: University of Ottawa
Marcus Conrad: Helmholtz Zentrum München

Nature, 2022, vol. 608, issue 7924, 778-783

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05022-3

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