Lactate Elicits ER-Mitochondrial Mg Dynamics to Integrate Cellular Metabolism.

Mg 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 Mg (Mg) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of Mg dynamics. Lactate emerged as an activator of rapid release of Mg from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg (Mg) 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 Mg dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated Mg entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits Mg uptake. Intriguingly, suppression of Mg surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes Mg and links the Mg transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.