Mishima, Eikan and Ito, Junya and Wu, Zijun and Nakamura, Toshitaka and Wahida, Adam and Doll, Sebastian and Tonnus, Wulf and Nepachalovich, Palina and Eggenhofer, Elke and Aldrovandi, Maceler and Henkelmann, Bernhard and Yamada, Ken-Ichi and Wanninger, Jonas and Zilka, Omkar and Sato, Emiko and Feederle, Regina and Hass, Daniela and Maida, Adriano and Mourao, Andre Santos Dias and Linkermann, Andreas and Geissler, Edward K. and Nakagawa, Kiyotaka and Abe, Takaaki and Fedorova, Maria and Proneth, Bettina and Pratt, Derek A. and Conrad, Marcus (2022) A non-canonical vitamin K cycle is a potent ferroptosis suppressor. NATURE, 608 (7924). 778-+. ISSN 0028-0836, 1476-4687
Full text not available from this repository. (Request a copy)Abstract
Biochemical and lipidomic analyses identify an anti-ferroptotic function of vitamin K and reveal ferroptosis suppressor protein 1 (FSP1) as the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle. Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation(1), has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers(2). 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 phylloquinone(3)-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for gamma-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 cycle(6). The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLUTATHIONE-PEROXIDASE 4; CELL-DEATH; LIPID-PEROXIDATION; ANTAGONISM; METABOLISM; ENZYMES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 13:43 |
| Last Modified: | 01 Feb 2024 13:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58391 |
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