GPX4
脂质过氧化
生物
DNA损伤
肌萎缩侧索硬化
细胞生物学
程序性细胞死亡
癌症研究
氧化应激
生物化学
谷胱甘肽过氧化物酶
超氧化物歧化酶
医学
细胞凋亡
病理
DNA
疾病
作者
Di Wang,Weiwei Liang,Di Huo,Hongyong Wang,Ying Wang,Chuanbo Cong,Chun‐Ting Zhang,Yan Shi,Ming Gao,Xiaoli Su,Xingli Tan,Wenmo Zhang,Han Liu,Dongmei Zhang,Honglin Feng
标识
DOI:10.1038/s41418-022-01089-7
摘要
Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferroptosis in ALS remains unclear. In this research, bioinformatics analysis revealed a high correlation between ALS, ferroptosis, and Speedy/RINGO cell cycle regulator family member A (SPY1). Lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was generated by TFR1-imported excess free iron, decreased GSH, mitochondrial membrane dysfunction, upregulated ALOX15, and inactivation of GCH1, GPX4. SPY1 is a "cyclin-like" protein that has been proved to enhance the viability of hSOD1G93A cells by inhibiting DNA damage. In our study, the decreased expression of SPY1 in ALS was resulted from unprecedented ubiquitination degradation mediated by MDM2 (a nuclear-localized E3 ubiquitin ligase). Further, SPY1 was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated GCH1/BH4 axis (a resistance axis of ferroptosis) and transferrin receptor protein 1 (TFR1)-induced iron. Additionally, neuron-specific overexpression of SPY1 significantly delayed the occurrence and prolonged the survival in ALS transgenic mice through the above two pathways. These results suggest that SPY1 is a novel target for both ferroptosis and ALS.
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