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

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

Cell (2020-10-10)
Cassidy C Daw, Karthik Ramachandran, Benjamin T Enslow, Soumya Maity, Brian Bursic, Matthew J Novello, Cherubina S Rubannelsonkumar, Ayah H Mashal, Joel Ravichandran, Terry M Bakewell, Weiwei Wang, Kang Li, Travis R Madaris, Christopher E Shannon, Luke Norton, Soundarya Kandala, Jeffrey Caplan, Subramanya Srikantan, Peter B Stathopulos, W Brian Reeves, Muniswamy Madesh
ABSTRACT

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.

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