小柯机器人

一个非经典的维生素K循环是一种有效的铁死亡抑制因子
2022-08-06 23:41
来源：小柯机器人

德国慕尼黑亥姆兹中心Marcus Conrad、Eikan Mishima等研究人员合作发现，一个非经典的维生素K循环是一种有效的铁死亡抑制因子。这一研究成果于2022年8月3日在线发表在国际学术期刊《自然》上。

研究人员发现，完全还原形式的维生素K（一组萘醌，包括甲萘醌和叶绿醌）除了作为γ-谷氨酰羧化酶的辅助因子而与血液凝固有关的常规功能外，还具有强大的抗铁死亡功能。铁死亡抑制蛋白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之后控制铁死亡的第二大支柱，被发现能有效地将维生素K还原成其氢醌，这是一种有效的自由基捕获抗氧化剂和（磷酸）脂质过氧化的抑制剂。FSP1介导的维生素K还原也是维生素K对华法林中毒解毒作用的原因。由此可见，FSP1是在经典的维生素K循环中介导抗华法林的维生素K还原酶。依赖FSP1的非经典维生素K循环可以起到保护细胞免受有害的脂质过氧化和铁死亡的作用。
 
据介绍，铁死亡是一种以铁依赖性脂质过氧化为标志的非凋亡性细胞死亡形式，在器官损伤、退行性疾病和耐药性癌症的脆弱性方面具有关键作用。尽管在了解与铁死亡有关的分子过程方面已经取得了实质性的进展，但决定细胞对铁死亡敏感性的其他细胞外在和内在过程仍然是未知的。
 
附：英文原文
 
Title: A non-canonical vitamin K cycle is a potent ferroptosis suppressor

Author: 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, Mouro, Andr Santos Dias, Linkermann, Andreas, Geissler, Edward K., Nakagawa, Kiyotaka, Abe, Takaaki, Fedorova, Maria, Proneth, Bettina, Pratt, Derek A., Conrad, Marcus

Issue&Volume: 2022-08-03

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.

DOI: 10.1038/s41586-022-05022-3

Source: https://www.nature.com/articles/s41586-022-05022-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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