Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca(2+) uptake and viability.

Mitochondrial Ca(2+) uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca(2+) transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca(2+) uptake. 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 that decreased matrix [Mg(2+)] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg(2+) in regulating MCU activity.