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

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