Intracellular magnesium level determines cell viability in the MPP+ model of Parkinson's disease

• MPP+ induced Mg2 + influx across cell membrane and Mg2 + release from mitochondria.
• Mg2 + influx resulted in the chronic increase in [Mg2 +]i and cellular total Mg2 +.
• Prevention of Mg2 + influx altered [Mg2 +]i during neurodegeneration.
• Viability of the cells exposed to MPP+ was determined depending on [Mg2 +]i.
• Increase in [Mg2 +]i attenuated ROS production and maintained ATP concentration.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from mitochondrial dysfunction in dopaminergic neurons. Mitochondria are believed to be responsible for cellular Mg2 + homeostasis. Mg2 + is indispensable for maintaining ordinal cellular functions, hence perturbation of the cellular Mg2 + homeostasis may be responsible for the disorders of physiological functions and diseases including PD. However, the changes in intracellular Mg2 + concentration ([Mg2 +]i) and the role of Mg2 + in PD have still been obscure. In this study, we investigated [Mg2 +]i and its effect on neurodegeneration in the 1-methyl-4-phenylpyridinium (MPP+) model of PD in differentiated PC12 cells. Application of MPP+ induced an increase in [Mg2 +]i immediately via two different pathways: Mg2 + release from mitochondria and Mg2 + influx across cell membrane, and the increased [Mg2 +]i sustained for more than 16 h after MPP+ application. Suppression of Mg2 + influx decreased the viability of the cells exposed to MPP+. The cell viability correlated highly with [Mg2 +]i. In the PC12 cells with suppressed Mg2 + influx, ATP concentration decreased and the amount of reactive oxygen species (ROS) increased after an 8 h exposure to MPP+. Our results indicate that the increase in [Mg2 +]i inhibited cellular ROS generation and maintained ATP production, which resulted in the protection from MPP+ toxicity.