Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism

Mg2+ is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes, To understand how the spatio-temporal dynamics of intracellular Mg2+ (Mg-i(2+)) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of Mg-i(2+) dynamics. Lactate emerged as an activator of rapid release of Mg2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg2+ (Mg-m(2+)) uptake in multiple cell types. We demonstrate that this process is remarkably temperature sensitive and mediated through intracellular but not extracellular signals. The ER-mitochondrial Mg2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated Mg-m(2+) entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits Mg-m(2+) uptake. Intriguingly, suppression of Mg-m(2+) surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes Mg-i(2+) and links the Mg-m(2+) transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.