Mitochondrial lipid peroxidation is necessary but not sufficient for induction of ferroptosis

IF 4.6 2区 生物学 Q2 CELL BIOLOGY Frontiers in Cell and Developmental Biology Pub Date : 2024-09-11 DOI:10.3389/fcell.2024.1452824
He Huan, Konstantin G. Lyamzaev, Alisa A. Panteleeva, Boris V. Chernyak
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Abstract

Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO.
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线粒体脂质过氧化是诱导铁变态反应的必要条件,但并非充分条件
铁中毒是由脂质过氧化(LPO)介导的一种调节性细胞死亡形式,由于其在癌症化疗中的潜在治疗应用及其在缺血性器官损伤中的病理生理作用,铁中毒已成为一项热门研究课题。线粒体脂质过氧化(LPO)在铁中毒中的作用仍然鲜为人知。我们的研究表明,以柠檬酸铁铵(FAC)的形式补充外源铁与丁硫磺酰亚胺(BSO,一种谷胱甘肽生物合成抑制剂)结合使用,可诱导线粒体脂质过氧化,而线粒体脂质过氧化先于正常人成纤维细胞的铁变态反应。线粒体靶向抗氧化剂 SkQ1 和氧化还原介质亚甲基蓝(可抑制线粒体电子传递链复合体 I 中活性氧(ROS)的产生)可防止线粒体脂质过氧化和铁沉降,但不会影响细胞膜 ROS 的积累。这些数据表明,线粒体脂质过氧化是外源铁诱导铁中毒所必需的。在没有 BSO 的情况下,FAC 可刺激线粒体过氧化,但不会降低细胞活力。BSO 消耗谷胱甘肽不会影响 FAC 诱导的线粒体 LPO,但会强烈刺激 ROS 在细胞质中的积累。这些数据让我们得出结论,线粒体 LPO 不足以导致铁卟啉沉积,细胞膜 ROS 介导了额外的氧化事件,与线粒体 LPO 一起刺激铁卟啉沉积。
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来源期刊
Frontiers in Cell and Developmental Biology
Frontiers in Cell and Developmental Biology Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
9.70
自引率
3.60%
发文量
2531
审稿时长
12 weeks
期刊介绍: Frontiers in Cell and Developmental Biology is a broad-scope, interdisciplinary open-access journal, focusing on the fundamental processes of life, led by Prof Amanda Fisher and supported by a geographically diverse, high-quality editorial board. The journal welcomes submissions on a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics, with sections focusing on signaling, adhesion, migration, cell death and survival and membrane trafficking. Additionally, the journal offers sections dedicated to the cutting edge of fundamental and translational research in molecular medicine and stem cell biology. With a collaborative, rigorous and transparent peer-review, the journal produces the highest scientific quality in both fundamental and applied research, and advanced article level metrics measure the real-time impact and influence of each publication.
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