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Updated: Jul 21, 2025

Analyses of Mitochondrial Calcium Influx in Isolated Mitochondria and Cultured Cells
Published on: April 27, 2018
Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca2+ uptake
Thiruvelselvan Ponnusamy1, Prema Velusamy1, Amrendra Kumar2
1Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.
Abstract:
Calcium (Ca2+) uptake by mitochondria is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. MCU is a heterooligomeric complex with a pore-forming component and accessory proteins required for channel activity. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed Mrs2 as the authentic mammalian mitochondrial Mg2+ channel using the planar lipid bilayer recordings. Using a liver-specific Mrs2 KO mouse model, we showed that decreased matrix [Mg2+] is associated with increased MCU activity and matrix Ca2+ overload. The disruption of Mg2+dependent MCU regulation significantly prompted mitochondrial permeability transition pore opening-mediated cell death during tissue IR injury. Our findings support a critical role for mMg2+ in regulating MCU activity and attenuating mCa2+ overload.
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