MRS2 is a pentameric magnesium transporter located in the inner mitochondrial membrane that mediates Mg2+ influx into the mitochondrial matrix and regulates cellular magnesium homeostasis 1. Beyond magnesium, MRS2 functions as a calcium-regulated, nonselective cation channel permeable to Mg2+, Ca2+, Na+, and K+ 1. Structurally, MRS2 contains two transmembrane domains forming the ion pore and a soluble amino-terminal domain (NTD) that functions as a regulatory feedback switch, with Mg2+ and calcium binding to the NTD suppressing channel oligomerization and activity 2. Key gating residues R332 and M336 control ion translocation through a hydrogen-bonding network 3. A conserved arginine ring within the pore restricts cation movement, preventing collapse of the mitochondrial proton gradient essential for ATP synthesis 1. MRS2 is required for normal respiratory complex I expression and plays a critical role in maintaining mitochondrial bioenergetics 3. Functionally, lactate activates MRS2-mediated mitochondrial magnesium uptake, linking metabolic feedback to mitochondrial function 4. Clinically, MRS2 dysregulation associates with cancer progression; elevated MRS2 in gastric cancer promotes multidrug resistance by suppressing apoptosis 5, while in endometrial cancer it correlates with enhanced ROS production and cell proliferation 6.