Shindo Yutaka, Yamanaka Ryu, Suzuki Koji, Hotta Kohji, Oka Kotaro
Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
Biochim Biophys Acta. 2015 Dec;1853(12):3182-91. doi: 10.1016/j.bbamcr.2015.08.013. Epub 2015 Aug 28.
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 8h 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.
帕金森病（PD）是一种由多巴胺能神经元线粒体功能障碍引起的神经退行性疾病。线粒体被认为负责细胞内镁离子（Mg²⁺）的稳态。Mg²⁺对于维持正常的细胞功能不可或缺，因此细胞内Mg²⁺稳态的紊乱可能是包括PD在内的生理功能障碍和疾病的原因。然而，细胞内Mg²⁺浓度（[Mg²⁺]i）的变化以及Mg²⁺在PD中的作用仍不清楚。在本研究中，我们在分化的PC12细胞的1-甲基-4-苯基吡啶离子（MPP⁺）PD模型中研究了[Mg²⁺]i及其对神经退行性变的影响。MPP⁺的应用通过两种不同途径立即导致[Mg²⁺]i升高：Mg²⁺从线粒体释放以及Mg²⁺跨细胞膜内流，并且在应用MPP⁺后升高的[Mg²⁺]i持续超过16小时。抑制Mg²⁺内流降低了暴露于MPP⁺的细胞的活力。细胞活力与[Mg²⁺]i高度相关。在Mg²⁺内流受到抑制的PC12细胞中，暴露于MPP⁺ 8小时后，ATP浓度降低，活性氧（ROS）量增加。我们的结果表明，[Mg²⁺]i的升高抑制了细胞ROS的产生并维持了ATP的生成，从而导致对MPP⁺毒性的保护作用。
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