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

Nature. 2022 Aug;608(7924):778-783. doi: 10.1038/s41586-022-05022-3.

Eikan Mishima ¹ ², Junya Ito ³, Zijun Wu ⁴, Toshitaka Nakamura ⁵, Adam Wahida ⁵, Sebastian Doll ⁵, Wulf Tonnus ⁶, Palina Nepachalovich ⁷ ⁸, Elke Eggenhofer ⁹, Maceler Aldrovandi ⁵, Bernhard Henkelmann ⁵, Ken-Ichi Yamada ¹⁰, Jonas Wanninger ⁵, Omkar Zilka ⁴, Emiko Sato ¹¹, Regina Feederle ¹², Daniela Hass ¹³, Adriano Maida ¹³, André Santos Dias Mourão ¹⁴, Andreas Linkermann ⁶, Edward K Geissler ⁹, Kiyotaka Nakagawa ³, Takaaki Abe ¹⁵ ¹⁶, Maria Fedorova ⁷ ⁸, Bettina Proneth ⁵, Derek A Pratt ⁴, Marcus Conrad ¹⁷

Affiliations

1 Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany. eikan@med.tohoku.ac.jp.
2 Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan. eikan@med.tohoku.ac.jp.
3 Laboratory of Food Function Analysis, Tohoku University, Sendai, Japan.
4 Department of Chemistry and Biomolecular Science, University of Ottawa, Ottawa, Ontario, Canada.
5 Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.
6 Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
7 Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University, Leipzig, Germany.
8 Zentrum Membranbiochemie und Lipidforschung, Medizinische Fakultät Carl Gustav Carus, Technical University, Dresden, Germany.
9 Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
10 Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
11 Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences, Sendai, Japan.
12 Monoclonal Antibody Core Facility, Helmholtz Zentrum München, Neuherberg, Germany.
13 Institute for Diabetes and Cancer, Helmholtz Zentrum München, Neuherberg, Germany.
14 Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
15 Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan.
16 Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
17 Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany. marcus.conrad@helmholtz-muenchen.de.

PMID: 35922516 DOI: 10.1038/s41586-022-05022-3

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-4^4,5, 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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