Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme involved in phospholipid peroxide repair and metabolism. In this study we investigated the global lipid composition of a human hepatocarcinoma cell line SNU475 lacking PRDX6 and lipid related cellular processes. There was a general decrease in multiple lipids species upon loss of PRDX6, in particular sphingomyelins and acylcarnitines, consistent with previously observed alterations in cell signaling pathways and mitochondrial dysfunction. Deprivation of docosahexaenoic acid and related species was also evident. However, a few striking exceptions are worth highlighting: 1) Three specific arachidonic acid (AA) containing phophatidylcholines (PC) increased significantly. The increase of sn1-stearic/sn2-PUFA containing PC and sn2-AA containing plasmenyls are indicative of a preference of PRDX6 iPLA2 activity for these AA storage glycerophospholipids. 2) Several polyunsaturated fatty acids (PUFA) and PUFA containing triacylglycerols accumulated together with increased formation of lipid droplets, an indication of altered FA flux and PUFA sequestration in PRDX6 knockout cells. Loss of PRDX6 resulted in increased sensitivity to erastin-induced ferroptosis, independent of selenium and GPX4, as a consequence of increased levels of lipid hydroperoxides, that reverted to normal levels upon rescue with PRDX6. The results presented demonstrate that all three enzymatic activities of PRDX6 contribute to the role of this multifunctional enzyme in diverse cellular processes, including membrane phospholipid remodeling and glycerophospholipid functional diversity, resulting in altered lipid peroxides and modulation of AA disposition and traffic. These contributions highlight the complexity of the changes that loss of PRDX6 exerts on cell functionality..

中文翻译：

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过氧化物还原蛋白 6 （PRDX6） 的缺失会改变脂质组成和分布，导致对铁死亡的敏感性增加。


过氧化物还原蛋白 6 （PRDX6） 是一种参与磷脂过氧化物修复和代谢的多功能酶。在这项研究中，我们研究了缺乏 PRDX6 和脂质相关细胞过程的人肝癌细胞系 SNU475 的整体脂质组成。PRDX6 丢失后，多种脂质种类普遍减少，特别是鞘磷脂和酰基肉碱，这与先前观察到的细胞信号通路和线粒体功能障碍的改变一致。二十二碳六烯酸和相关物种的剥夺也很明显。然而，一些引人注目的例外值得强调：1） 三种含有磷脂酰胆碱 （PC） 的特定花生四烯酸 （AA） 显着增加。含有 PC 的 sn1-硬脂酸/sn2-PUFA 和含有 sn2-AA 的血浆酰的增加表明 PRDX6 iPLA2 活性对这些 AA 储存甘油磷脂的偏好。2） 几种含有三酰基甘油的多不饱和脂肪酸 （PUFA） 和 PUFA 一起积累，脂滴形成增加，这表明 PRDX6 敲除细胞中 FA 通量和 PUFA 隔离改变。PRDX6 的缺失导致对 erastin 诱导的铁死亡的敏感性增加，独立于硒和 GPX4，这是脂质氢过氧化物水平增加的结果，在用 PRDX6 抢救后恢复到正常水平。提出的结果表明，PRDX6 的所有三种酶活性都有助于这种多功能酶在多种细胞过程中的作用，包括膜磷脂重塑和甘油磷脂功能多样性，导致脂质过氧化物改变并调节 AA 处置和运输。 这些贡献突出了PRDX6缺失对细胞功能的影响的复杂性。