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

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. 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. 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.