Excessive Mg2+Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species

Aims: Mg2+ is fundamental for life, and its shortage severely impairs vital functions. However, whether excessive Mg2+ has beneficial or adverse effects has remained unknown. To clarify this issue, we analyzed the effect of suppressing the functions of Cyclin M (CNNM) Mg2+ efflux transporters in various experimental systems. Results: Investigation of short-lived Caenorhabditis elegans worms mutated for CNNM genes revealed reactive oxygen species (ROS) augmentation in intestinal cells, coincidently with high levels of Mg2+. Knockdown of gtl-1, encoding Mg2+-incorporating channel into intestinal cells, reduced ROS levels and restored life span, confirming the causative role of excessive Mg2+. 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 Mg2+ stimulates adenosine triphosphate overproduction and accelerates mitochondrial electron transport, whose suppression shut down ROS generation. Innovation and Conclusion: These results provide definitive evidence that excessive Mg2+ drives overproduction of ROS by affecting energy metabolism, implying the crucial importance of the tight regulation of intracellular Mg2+ levels.