Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis

谷胱甘肽 氧化应激 细胞生物学 GPX4 程序性细胞死亡 基因敲除 铁蛋白 脂质过氧化 化学 细胞 生物 细胞凋亡 活性氧 生物化学 超氧化物歧化酶 谷胱甘肽过氧化物酶
作者
Zixuan Liu,Xuying Lv,Erqun Song,Yang Song
出处
期刊:Toxicology and Applied Pharmacology [Elsevier]
卷期号:407: 115241-115241 被引量:45
标识
DOI:10.1016/j.taap.2020.115241
摘要

Neurological diseases were often characterized by progressive neuronal death, and emerging evidences suggested that ferroptosis may be an active driver of multiple neurodegenerative diseases. However, the mechanisms underlying ferroptosis in neuron cells are unclear. Here, we demonstrated that ferroptotic stimuli caused injury in neuron-like PC12 cells by modulating the expression of proteins involved in iron metabolism and lipid peroxidation at multiple levels, such as altering iron import/export, activating ferritinophagy, and decreasing glutathione (GSH) level. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple genes involved in ferroptosis, however, its exact role remain elusive. Our mechanistic inquiry revealed that Nrf2 expression enhanced iron storage capacity by increasing ferritin heavy chain 1 (FTH1) expression in PC12 cells. Moreover, Nrf2 alleviated the decrease in GSH level by promoting the expression of genes related to GSH synthesis, including solute carrier family 7 member 11 (SLC7A11) and cysteine ligase (GCL). The contribution of Nrf2 on ferroptosis resistance was further verified by increasing cell tolerance to oxidative stress. Furthermore, Nfe2l2 (Nrf2) knockdown sensitized cells to ferroptotic cell death. Taken together, our findings suggested that iron accumulation caused by altering iron metabolism and the decrease of GSH content are key factors in determining ferroptosis in PC12 cells, and Nrf2 inhibits ferroptosis by combating iron-induced oxidative stress. Our present study provided new clues for the intervention and prevention against ferroptosis-associated neurological diseases.
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