Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Antioxid Redox Signal. 2020 Jul 1;33(1):20-34. doi: 10.1089/ars.2019.7951. Epub 2020 Apr 8.
Mg is fundamental for life, and its shortage severely impairs vital functions. However, whether excessive Mg has beneficial or adverse effects has remained unknown. To clarify this issue, we analyzed the effect of suppressing the functions of Cyclin M (CNNM) Mg efflux transporters in various experimental systems. Investigation of short-lived worms mutated for CNNM genes revealed reactive oxygen species (ROS) augmentation in intestinal cells, coincidently with high levels of Mg. Knockdown of , encoding Mg-incorporating channel into intestinal cells, reduced ROS levels and restored life span, confirming the causative role of excessive Mg. Also, inactivation of orthologous CNNM in human cultured cells and mice by RNA interference, expression of CNNM-inhibiting protein, phosphatase of regenerating liver 3, or gene knockout resulted in ROS overproduction. Moreover, biochemical analyses revealed that excessive Mg stimulates adenosine triphosphate overproduction and accelerates mitochondrial electron transport, whose suppression shut down ROS generation. These results provide definitive evidence that excessive Mg drives overproduction of ROS by affecting energy metabolism, implying the crucial importance of the tight regulation of intracellular Mg levels.
镁是生命所必需的，其缺乏会严重损害重要的功能。然而，过量的镁是否有益或有害的影响仍然未知。为了澄清这个问题，我们分析了抑制细胞周期蛋白 M (CNNM)镁外排转运蛋白在各种实验系统中的功能的效果。对短寿命的突变体进行研究，这些突变体的 CNNM 基因发生了突变，结果发现肠道细胞中活性氧 (ROS) 的增加，同时伴有高水平的镁。将编码镁整合通道的基因敲低到肠道细胞中，降低了 ROS 水平并恢复了寿命，这证实了过量镁的因果作用。此外，通过 RNA 干扰使人类培养细胞和小鼠中的同源 CNNM 失活、表达 CNNM 抑制蛋白、肝再生磷酸酶 3 或基因敲除，也会导致 ROS 过度产生。此外，生化分析表明，过量的镁通过影响能量代谢刺激三磷酸腺苷的过度产生，并加速线粒体电子传递，而其抑制作用则会阻止 ROS 的产生。这些结果提供了确凿的证据，证明过量的镁通过影响能量代谢来驱动 ROS 的过度产生，这意味着严格调节细胞内镁水平的至关重要性。
