Cadmium induces mitochondrial ROS inactivation of XIAP pathway leading to apoptosis in neuronal cells.
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.
['Zhao|Rui|R|', 'Yu|Qianyun|Q|', 'Hou|Long|L|', 'Dong|Xiaoqing|X|', 'Zhang|Hai|H|', 'Chen|Xiaoling|X|', 'Zhou|Zhihan|Z|', 'Ma|Jing|J|', 'Huang|Shile|S|', 'Chen|Long|L|']
D017209:Apoptosis D002104:Cadmium D006801:Humans D008928:Mitochondria D017382:Reactive Oxygen Species D051636:X-Linked Inhibitor of Apoptosis Protein
Cadmium ROS XIAP Apoptosis Neuronal cells