Lactate is an Innate Activator of Mitochondrial Mg2+ Channel to integrate Cellular Metabolism

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Lactate is an Innate Activator of Mrs2-Mediated Mitochondrial Mg2+ Uptake to integrate Cellular Metabolism 


Mitochondria integrate myriad of signals including bioenergetics, oxidative signaling and ion homeostasis. The magnesium ion (Mg2+) is the most abundant and vital divalent cation in metazoans and is an essential cofactor for ATP, nucleic acids, and metabolic enzymes. Although Mg2+ is essential for the cellular functions, it remains a major question how the dynamics of intracellular Mg2+ ([Mg2+]i) control signaling systems in a spatio-temporal fashion. Due to nonidentification of ligand/activator of [Mg2+]i dynamics, we conducted a comprehensive screen to identify whether endogenous metabolites could function as activators of mitochondrial Mg2+ dynamics. Here, we identified glycolysis end-product lactate is the activator of mitochondrial Mg2+ uptake. This phenomenon is due to a rapid depletion of ER Mg2+ through lactate stimulation in multiple cell types.  We also demonstrated that lactate-induced rapid ER depletion and mitochondrial Mg2+ uptake is dose dependent and temperature sensitive. Lactate-induced mitochondrial Mg2+ uptake is intracellular but not extracellular mediated signals. Using pharmacological and genetic approaches, we show that lactate-mediated mitochondrial Mg2+ entry is Mrs2 and membrane dependent.  These findings together reveal our identification of the lactate dependent and temperature sensitive mitochondrial Mg2+ transporter possibly links metabolism feedback loop and mitochondrial energetics. 


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