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Impaired homeostasis of lysosomal Ca 2+  causes lysosome dysfunction and lysosomal storage diseases (LSDs), but the mechanisms by which lysosomes acquire and refill Ca 2+  are not known. We developed a physiological assay to monitor lysosomal Ca 2+  store refilling using specific activators of lysosomal Ca 2+  channels to repeatedly induce lysosomal Ca 2+  release. In contrast to the prevailing view that lysosomal acidification drives Ca 2+  into the lysosome, inhibiting the V-ATPase H +  pump did not prevent Ca 2+  refilling. Instead, pharmacological depletion or chelation of Endoplasmic Reticulum (ER) Ca 2+  prevented lysosomal Ca 2+  stores from refilling. More specifically, antagonists of ER IP3 receptors (IP3Rs) rapidly and completely blocked Ca 2+  refilling of lysosomes, but not in cells lacking IP3Rs. Furthermore, reducing ER Ca 2+  or blocking IP3Rs caused a dramatic LSD-like lysosome storage phenotype. By closely apposing each other, the ER may serve as a direct and primary source of Ca 2+ for the lysosome.

The endoplasmic reticulum, not the pH gradient, drives calcium refilling of lysosomes