Cadmium (Cd), a heavy metal pollutant, contributes to neurodegenerative disorders. Recently, we have demonstrated that Cd induction of reactive oxygen species (ROS) causes apoptosis in neuronal cells. Whether X-linked inhibitor of apoptosis protein (XIAP) is involved in Cd-induced ROS-dependent neuronal apoptosis remains unclear. Here, we show that Cd-induced ROS reduced the expression of XIAP, which resulted in up-regulation of murine double minute 2 homolog (MDM2) and down-regulation of p53, leading to apoptosis in PC12 cells and primary neurons. Inhibition of MDM2 with Nutlin-3a reversed Cd-induced reduction of p53 and substantially rescued cells from excess ROS-dependent death. Overexpression of XIAP protected against Cd induction of ROS-dependent neuronal apoptosis. Inhibition of XIAP by Embelin strengthened Cd-induced ROS and apoptosis in the cells. Furthermore, we found that Cd inactivation of XIAP pathway was attributed to Cd induction of mitochondrial ROS, as evidenced by using a mitochondrial superoxide indicator MitoSOX and a mitochondria-targeted antioxidant Mito-TEMPO. Taken together, these results indicate that Cd induces mitochondrial ROS inactivation of XIAP-MDM2-p53 pathway leading to apoptosis in neuronal cells. Our findings suggest that activators of XIAP or modulation of XIAP-MDM2-p53 pathway by antioxidants may be exploited for the prevention of Cd-induced oxidative stress and neurodegenerative diseases.

重金属污染物镉（Cd）会导致神经退行性疾病。最近，我们已经证明Cd诱导活性氧（ROS）诱导神经元细胞凋亡。X连锁的凋亡蛋白抑制剂（XIAP）是否参与Cd诱导的ROS依赖性神经元凋亡尚不清楚。在这里，我们显示镉诱导的ROS降低了XIAP的表达，从而导致了鼠双分2同源物（MDM2）的上调和p53的下调，从而导致PC12细胞和原代神经元的凋亡。用Nutlin-3a抑制MDM2可逆转Cd诱导的p53减少，并从过度的ROS依赖性死亡中大量拯救了细胞。XIAP的过表达可防止Cd诱导ROS依赖性神经元凋亡。Embelin对XIAP的抑制作用增强了Cd诱导的ROS和细胞凋亡。此外，我们发现，通过使用线粒体超氧化物指示剂MitoSOX和靶向线粒体的抗氧化剂Mito-TEMPO可以证明，XIAP途径的Cd失活归因于Cd诱导的线粒体ROS。综上所述，这些结果表明Cd诱导了XIAP-MDM2-p53途径的线粒体ROS失活，从而导致神经元细胞凋亡。我们的发现表明，可以利用XIAP激活剂或通过抗氧化剂调节XIAP-MDM2-p53途径来预防Cd诱导的氧化应激和神经退行性疾病。如使用线粒体超氧化物指示剂MitoSOX和靶向线粒体的抗氧化剂Mito-TEMPO所证明的。综上所述，这些结果表明Cd诱导了XIAP-MDM2-p53途径的线粒体ROS失活，从而导致神经元细胞凋亡。我们的发现表明，可以利用XIAP激活剂或通过抗氧化剂调节XIAP-MDM2-p53途径来预防Cd诱导的氧化应激和神经退行性疾病。如使用线粒体超氧化物指示剂MitoSOX和靶向线粒体的抗氧化剂Mito-TEMPO所证明的。综上所述，这些结果表明Cd诱导了XIAP-MDM2-p53途径的线粒体ROS失活，从而导致神经元细胞凋亡。我们的发现表明，可以利用XIAP激活剂或通过抗氧化剂调节XIAP-MDM2-p53途径来预防Cd诱导的氧化应激和神经退行性疾病。