Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism
Published:October 08, 2020DOI:
https://doi.org/10.1016/j.cell.2020.08.049
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Highlights
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L-lactate triggers ER Mg 2+ release that promotes mitochondrial Mg 2+ uptake
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Mg 2+ is a second messenger for metabolic circuits
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Limiting Mrs2-mediated Mg 2+ uptake enhances mitochondrial bioenergetics
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Inflammation-induced lactate contributes to organ failure via mMg 2+ surge
Summary
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+ ( iMg 2+) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of iMg 2+ dynamics. Lactate emerged as an activator of rapid release of Mg 2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg 2+ ( mMg 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 mMg 2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits mMg 2+ uptake. Intriguingly, suppression of mMg 2+ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes iMg 2+ and links the mMg 2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.
