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.