A computational model of lysosome-ER Ca2+ microdomains

Abstract

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 may allow formation of Ca2+ microdomains, though their size renders observation of Ca2+ dynamics impractical. We generated a computational model of lysosome-ER coupling that incorporated a previous model of the 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 microdomain Ca2+ need not be higher than 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.