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.