A computational model of lysosome-ER Ca2+ microdomains.

Acidic organelles form an important intracellular Ca2+ pool that can drive global Ca2+ signals through coupling with endoplasmic reticulum (ER) Ca2+ stores. Recently identified lysosome-ER membrane contact sites might allow formation of Ca2+ microdomains, although their size renders observation of Ca2+ dynamics impractical. Here, we generated a computational model of lysosome-ER coupling that incorporated a previous model of the inositol trisphosphate (IP3) receptor as the ER Ca2+ 'amplifier' and lysosomal leaks as the Ca2+ 'trigger'. The model qualitatively described global Ca2+ responses to the lysosomotropic agent GPN, which caused a controlled but substantial depletion of small solutes from the lysosome. Adapting this model to physiological lysosomal leaks induced by the Ca2+ mobilising messenger NAADP demonstrated that lysosome-ER microdomains are capable of driving global Ca2+ oscillations. Interestingly, our simulations suggest that the microdomain [Ca2+] need not be higher than that in the cytosol for responses to occur, thus matching the relatively high affinity of IP3 receptors for Ca2+. The relative distribution and overall density of the lysosomal leaks dictated whether microdomains triggered or modulated global signals. Our data provide a computational framework for probing lysosome-ER Ca2+ dynamics.