Excessive Mg Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species.

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.