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

Mg 2+ 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 2+ ( i Mg 2+ ) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of i Mg 2+ dynamics. Lactate emerged as an activator of rapid release of Mg 2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg 2+ ( m Mg 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 Mg 2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated m Mg 2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits m Mg 2+ uptake. Intriguingly, suppression of m Mg 2+ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes i Mg 2+ and links the m Mg 2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.