Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China.
School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Toxicol In Vitro. 2021 Jun;73:105146. doi: 10.1016/j.tiv.2021.105146. Epub 2021 Mar 15.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and striatum. Aging is the most important risk factor of PD. Ferroptosis is an iron-dependent form of cell death associated with PD. However, it is not clear whether ferroptosis accelerates PD by promoting cellular senescence. This study investigated the mechanism of 1-methyl-4-phenylpyridinium (MPP) -induced PC12 cells injury. We found that MPP induced cell senescence with increased β-galactosidase activity and the expression of p53, p21 and p16 activation in cells. In addition, MPP treatment showed smaller mitochondria and increased membrane density, downregulation of ferritin heavy chain 1 expression and upregulation of acyl-CoA synthetase long chain family member 4 expression, and enhanced levels of oxidative stress, which were important characteristics of ferroptosis. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was tested to eliminate MPP-induced cell senescence. Fer-1 downregulated the expression of p53 and upregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase-4 (GPX4) in MPP-induced ferroptosis. Inhibition of p53 eliminated cell senescence by upregulation the expression of of SLC7A11 and GPX4. Thus, these results suggest that MPP induces senescence in PC12 cells via the p53/ SLC7A11/ GPX4 signaling pathway in the ferroptosis regulation mechanism.
帕金森病（PD）的特征是黑质和纹状体多巴胺能神经元的丧失。衰老是 PD 的最重要危险因素。铁死亡是一种与 PD 相关的铁依赖性细胞死亡形式。然而，铁死亡是否通过促进细胞衰老加速 PD 尚不清楚。本研究探讨了 1-甲基-4-苯基吡啶（MPP）诱导 PC12 细胞损伤的机制。我们发现 MPP 诱导细胞衰老，细胞内β-半乳糖苷酶活性增加，p53、p21 和 p16 激活表达增加。此外，MPP 处理显示较小的线粒体和增加的膜密度，下调铁蛋白重链 1 的表达和上调酰基辅酶 A 合成酶长链家族成员 4 的表达，并增强氧化应激水平，这是铁死亡的重要特征。铁死亡抑制剂 Fer-1 用于测试消除 MPP 诱导的细胞衰老。Fer-1 下调 MPP 诱导的铁死亡中 p53 的表达，上调溶质载体家族 7 成员 11（SLC7A11）和谷胱甘肽过氧化物酶 4（GPX4）的表达。抑制 p53 通过上调 SLC7A11 和 GPX4 的表达消除细胞衰老。因此，这些结果表明，MPP 通过铁死亡调节机制中的 p53/SLC7A11/GPX4 信号通路诱导 PC12 细胞衰老。
