A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
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DOI：
10.1038/s41586-022-05022-3
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Conrad, Marcus
中科院分区：
文献类型：
--
作者：
Mishima, Eikan;Ito, Junya;Wu, Zijun;Nakamura, Toshitaka;Wahida, Adam;Doll, Sebastian;Tonnus, Wulf;Nepachalovich, Palina;Eggenhofer, Elke;Aldrovandi, Maceler;Henkelmann, Bernhard;Yamada, Ken-Ichi;Wanninger, Jonas;Zilka, Omkar;Sato, Emiko;Feederle, Regina;Hass, Daniela;Maida, Adriano;Mourao, Andre Santos Dias;Linkermann, Andreas;Geissler, Edward K.;Nakagawa, Kiyotaka;Abe, Takaaki;Fedorova, Maria;Proneth, Bettina;Pratt, Derek A.;Conrad, Marcus
铁凋亡是一种以铁依赖性脂质过氧化为特征的非凋亡细胞死亡形式，在器官损伤、退行性疾病和治疗耐药癌症的易感性中起关键作用。尽管在了解与铁下垂相关的分子过程方面取得了实质性进展，但决定细胞对铁下垂敏感性的额外细胞外部和细胞内部过程仍然未知。在这里，我们展示了完全还原形式的维生素k -一组萘醌，包括甲基萘醌和叶绿醌-除了作为γ-谷氨酰羧化酶的辅助因子与血液凝固相关的传统功能外，还具有强大的抗铁溶功能。铁衰亡抑制蛋白1 （FSP1）是一种NAD(P) h -泛醌还原酶，是继谷胱甘肽过氧化物酶-4之后控制铁衰亡的第二支柱，它被发现能有效地将维生素K还原为对苯二酚，对苯二酚是一种有效的自由基捕获抗氧化剂和（磷）脂质过氧化抑制剂。fsp1介导的维生素K的减少也是维生素K对华法林中毒的解毒作用的原因。由此可见，FSP1是规范维生素K循环中介导华法林抗性维生素K减少的酶。依赖于fsp1的非规范维生素K循环可以保护细胞免受有害的脂质过氧化和铁凋亡。生化和脂质组学分析确定了维生素K的抗铁沉功能，并揭示了铁沉抑制蛋白1 （FSP1）是规范维生素K循环中介导华法林抗性维生素K减少的酶。
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers. 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—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, 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. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis. 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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
16
作者：
Rodriguez, Raphae;Schreiber, Stuart L.;Conrad, Marcus
通讯作者：
Conrad, Marcus
DOI：
10.1073/pnas.1415518111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Linkermann, Andreas;Skouta, Rachid;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
15
作者：
Li, Bo;Harjani, Jitendra R.;Pratt, Derek A.
通讯作者：
Pratt, Derek A.