Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca(2+) uptake

Calcium (Ca(2+)) uptake by mitochondria is essential in regulating bioenergetics, cell death, and cytosolic Ca(2+) transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca(2+) 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 Mg(2+)-dependent regulation of MCU activity. We showed Mrs2 as the authentic mammalian mitochondrial Mg(2+) channel using the planar lipid bilayer recordings. Using a liver-specific Mrs2 KO mouse model, we showed that decreased matrix [Mg(2+)] is associated with increased MCU activity and matrix Ca(2+) overload. The disruption of Mg(2+)dependent MCU regulation significantly prompted mitochondrial permeability transition pore opening-mediated cell death during tissue IR injury. Our findings support a critical role for mMg(2+) in regulating MCU activity and attenuating mCa(2+) overload.