Loss of peroxiredoxin 6 alters lipid composition and distribution resulting in increased sensitivity to ferroptosis.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Daniel J Lagal, Ángel Ortiz-Alcántara, José R Pedrajas, Brian McDonagh, J Antonio Bárcena, Raquel Requejo-Aguilar, C Alicia Padilla
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引用次数: 0

Abstract

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.

过氧化物歧化酶 6 (PRDX6) 的缺失会改变脂质的组成和分布,从而增加对铁中毒的敏感性。
过氧化物歧化酶 6(Peroxiredoxin 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 的人肝癌细胞系 SNU475 的总体脂质组成以及与脂质相关的细胞过程。PRDX6缺失后,多种脂类普遍减少,尤其是鞘磷脂和酰基肉碱,这与之前观察到的细胞信号通路和线粒体功能障碍的改变一致。对二十二碳六烯酸和相关物质的剥夺也很明显。然而,有几个显著的例外值得强调:1) 三种含有特定花生四烯酸(AA)的酞酰胆碱(PC)显著增加。含有 sn1-硬脂酸/sn2-PUFA 的 PC 和含有 sn2-AA 的 plasmenyls 的增加表明 PRDX6 iPLA2 活性偏好这些 AA 储存甘油磷脂。2)在 PRDX6 基因敲除细胞中,几种多不饱和脂肪酸(PUFA)和含 PUFA 的三酰甘油积累,同时脂滴的形成增加,这表明 FA 通量和 PUFA 封存发生了改变。由于脂质氢过氧化物水平的增加,PRDX6 基因缺失导致对麦拉宁诱导的铁中毒的敏感性增加,这与硒和 GPX4 无关。研究结果表明,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发挥作用,包括膜磷脂重塑和甘油磷脂功能多样性,从而导致脂质过氧化物的改变以及 AA 的处置和运输调节。这些贡献凸显了缺失 PRDX6 对细胞功能所产生变化的复杂性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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