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⁺ (_iMg²⁺) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of _iMg²⁺ dynamics. Lactate emerged as an activator of rapid release of Mg²⁺ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg²⁺ (_mMg²⁺) 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 _mMg²⁺ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits _mMg²⁺ uptake. Intriguingly, suppression of _mMg²⁺ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes _iMg²⁺ and links the _mMg²⁺ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.