A computational model of lysosome-ER Ca2+ microdomains.

ABSTRACT Acidic organelles form an important intracellular Ca 2+ pool that can drive global Ca 2+ signals through coupling with endoplasmic reticulum (ER) Ca 2+ stores. Recently identified lysosome–ER membrane contact sites might allow formation of Ca 2+ microdomains, although their size renders observation of Ca 2+ dynamics impractical. Here, we generated a computational model of lysosome–ER coupling that incorporated a previous model of the inositol trisphosphate (IP 3 ) receptor as the ER Ca 2+ ‘amplifier’ and lysosomal leaks as the Ca 2+ ‘trigger’. The model qualitatively described global Ca 2+ 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 Ca 2+ mobilising messenger NAADP demonstrated that lysosome–ER microdomains are capable of driving global Ca 2+ oscillations. Interestingly, our simulations suggest that the microdomain [Ca 2+ ] need not be higher than that in the cytosol for responses to occur, thus matching the relatively high affinity of IP 3 receptors for Ca 2+ . 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 Ca 2+ dynamics.