Calcium and magnesium deficiency induces stress granule formation to maintain magnesium homeostasis

Hypocalcemia and hypomagnesemia frequently occur under pathological conditions such as Crohn's disease or during diuretic treatment. However, how the combined deficiency of Ca²⁺ and Mg²⁺ affects cellular physiology has remained unclear. In this study, we focused on this issue and found that Ca²⁺/Mg²⁺ deprivation is a potent driver of stress granule (SG) formation. When SG formation was inhibited by G3BP1/2 knockdown, Ca²⁺/Mg²⁺ deprivation caused a further decrease in intracellular Mg²⁺ levels and an increase in cell death, indicating that SGs function to mitigate Mg²⁺ loss and protect cells from death under cation-deficient conditions. Furthermore, we found that the expression of the Mg²⁺ transporter MAGT1 is upregulated in an SG-dependent manner, and that MAGT1 knockdown further decreases intracellular Mg²⁺ levels and increases cell death. Collectively, our results demonstrate that SG formation acts as an adaptive mechanism to maintain Mg²⁺ homeostasis during Ca²⁺/Mg²⁺ deficiency.