脂质过氧化和铁代谢：铁死亡稳态控制的两个基石。,International Journal of Molecular Sciences

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脂质过氧化和铁代谢：铁死亡稳态控制的两个基石。
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2022-12-27 , DOI: 10.3390/ijms24010449
Luc Rochette ₁ , Geoffrey Dogon ₁ , Eve Rigal ₁ , Marianne Zeller ₁ , Yves Cottin ₂ , Catherine Vergely ₁

Affiliation

调节性细胞死亡 (RCD) 对发育、组织稳态和各种疾病的发生具有重要影响。在不同形式的 RCD 中，铁死亡被认为是一种活性氧 (ROS) 依赖性调节性坏死。ROS 可通过形成脂质自由基 L• 与脂质 (L) 膜的多不饱和脂肪酸 (PUFA) 反应，并诱导脂质过氧化形成 L-ROS。铁死亡是由脂质氢过氧化物 (LOOH) 解毒和铁依赖性 L-ROS 积累之间的不平衡引发的。细胞内铁积累和脂质过氧化是导致铁死亡的两个主要生化事件。包括线粒体和溶酶体在内的细胞器参与了铁死亡过程中铁代谢和氧化还原失衡的调节。在这篇评论中，我们将概述脂质过氧化，以及铁死亡级联中涉及的关键成分。减少ROS的主要机制是谷胱甘肽（GSH）的氧化还原能力。GSH 是一种三肽，包括谷氨酸、半胱氨酸和甘氨酸，可作为抗氧化剂，是谷胱甘肽过氧化物酶 4 (GPX4) 的底物，后者随后会转化为氧化型谷胱甘肽 (GSSG)。增加 GSH 的表达可以抑制铁死亡。我们强调 xc-GSH-GPX4 通路作为调节铁死亡的主要通路的作用。xc- 系统由亚基溶质载体家族成员（SLC7A11 和 SLC3A2）组成，介导胱氨酸和谷氨酸跨质膜交换以合成 GSH。越来越多的证据表明铁死亡需要自噬机制来执行。铁蛋白自噬用于描述自噬机制去除主要的铁储存蛋白铁蛋白。核受体共激活因子 4 (NCOA4) 是一种细胞溶质自噬受体，用于结合铁蛋白，随后被铁蛋白吞噬作用降解。在铁蛋白吞噬过程中，释放的储存铁可用于生物合成途径。功能失调的铁死亡反应与多种病理状况有关。已经开发出靶向氧化还原或铁代谢相关蛋白和信号转导的铁死亡诱导剂或抑制剂。同时检测细胞内和细胞外标记物可能有助于诊断和治疗与铁死亡相关的疾病。核受体共激活因子 4 (NCOA4) 是一种细胞溶质自噬受体，用于结合铁蛋白，随后被铁蛋白吞噬作用降解。在铁蛋白吞噬过程中，释放的储存铁可用于生物合成途径。功能失调的铁死亡反应与多种病理状况有关。已经开发出靶向氧化还原或铁代谢相关蛋白和信号转导的铁死亡诱导剂或抑制剂。同时检测细胞内和细胞外标记物可能有助于诊断和治疗与铁死亡相关的疾病。核受体共激活因子 4 (NCOA4) 是一种细胞溶质自噬受体，用于结合铁蛋白，随后被铁蛋白吞噬作用降解。在铁蛋白吞噬过程中，释放的储存铁可用于生物合成途径。功能失调的铁死亡反应与多种病理状况有关。已经开发出靶向氧化还原或铁代谢相关蛋白和信号转导的铁死亡诱导剂或抑制剂。同时检测细胞内和细胞外标记物可能有助于诊断和治疗与铁死亡相关的疾病。功能失调的铁死亡反应与多种病理状况有关。已经开发出靶向氧化还原或铁代谢相关蛋白和信号转导的铁死亡诱导剂或抑制剂。同时检测细胞内和细胞外标记物可能有助于诊断和治疗与铁死亡相关的疾病。功能失调的铁死亡反应与多种病理状况有关。已经开发出靶向氧化还原或铁代谢相关蛋白和信号转导的铁死亡诱导剂或抑制剂。同时检测细胞内和细胞外标记物可能有助于诊断和治疗与铁死亡相关的疾病。

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Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis.

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the xc- GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system xc-, composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage.

更新日期：2022-12-27

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