Magnesium uptake by connecting fluid-phase endocytosis to an intracellular inorganic cation filter

Cells acquire free metals through plasma membrane transporters. But, in natural settings, sequestering agents often render metals inaccessible to transporters, limiting metal bioavailability. Here we identify a pathway for metal acquisition, allowing cells to cope with this situation. Under limited bioavailability of Mg²⁺, yeast cells upregulate fluid-phase endocytosis and transfer solutes from the environment into their vacuole, an acidocalcisome-like compartment loaded with highly concentrated polyphosphate. We propose that this anionic inorganic polymer, which is an avid chelator of Mg²⁺, serves as an immobilized cation filter that accumulates Mg²⁺ inside these organelles. It thus allows the vacuolar exporter Mnr2 to efficiently transfer Mg²⁺ into the cytosol. Leishmania parasites also employ acidocalcisomal polyphosphate to multiply in their Mg²⁺-limited habitat, the phagolysosomes of inflammatory macrophages. This suggests that the pathway for metal uptake via endocytosis, acidocalcisomal polyphosphates and export into the cytosol, which we term EAPEC, is conserved.