Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca²⁺ uptake and viability

Mitochondrial Ca²⁺ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca²⁺ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca²⁺ 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 Mg²⁺-dependent regulation of MCU activity. We showed that decreased matrix [Mg²⁺] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg²⁺ in regulating MCU activity.