Modeling the role of endoplasmic reticulum-mitochondria microdomains in calcium dynamics

Upon inositol trisphosphate (IP 3 ) stimulation of non-excitable cells, including vascular endothelial cells, calcium (Ca 2+ ) shuttling between the endoplasmic reticulum (ER) and mitochondria, facilitated by complexes called Mitochondria-Associated ER Membranes (MAMs), is known to play an important role in the occurrence of cytosolic Ca 2+ concentration ([Ca 2+ ] Cyt ) oscillations. A mathematical compartmental closed-cell model of Ca 2+ dynamics was developed that accounts for ER-mitochondria Ca 2+ microdomains as the µd compartment (besides the cytosol, ER and mitochondria), Ca 2+ influx to/efflux from each compartment and Ca 2+ buffering. Varying the distribution of functional receptors in MAMs vs. the rest of ER/mitochondrial membranes, a parameter called the channel connectivity coefficient (to the µd), allowed for generation of [Ca 2+ ] Cyt oscillations driven by distinct mechanisms at various levels of IP 3 stimulation. Oscillations could be initiated by the transient opening of IP 3 receptors facing either the cytosol or the µd, and subsequent refilling of the respective compartment by Ca 2+ efflux from the ER and/or the mitochondria. Only under conditions where the µd became the oscillation-driving compartment, silencing the Mitochondrial Ca 2+ Uniporter led to oscillation inhibition. Thus, the model predicts that alternative mechanisms can yield [Ca 2+ ] Cyt oscillations in non-excitable cells, and, under certain conditions, the ER-mitochondria µd can play a regulatory role.