Mitochondrial calcium handling within the interstitial cells of Cajal

The interstitial cells of Cajal (ICC) drive rhythmic pacemaking contractions in the gastrointestinal system. The ICC generate pacemaking signals by membrane depolarizations associated with the release of intracellular calcium (Ca(2+)) in the endoplasmic reticulum (ER) through inositol-trisphosphate (IP3) receptors (IP3R) and uptake by mitochondria (MT). This Ca(2+) dynamic is hypothesized to generate pacemaking signals by calibrating ER Ca(2+) store depletions and membrane depolarization with ER store-operated Ca(2+) entry mechanisms. Using a biophysically based spatio-temporal model of integrated Ca(2+) transport in the ICC, we determined the feasibility of ER depletion timescale correspondence with experimentally observed pacemaking frequencies while considering the impact of IP3R Ca(2+) release and MT uptake on bulk cytosolic Ca(2+) levels because persistent elevations of free intracellular Ca(2+) are toxic to the cell. MT densities and distributions are varied in the model geometry to observe MT influence on free cytosolic Ca(2+) and the resulting frequencies of ER Ca(2+) store depletions, as well as the sarco-endoplasmic reticulum Ca(2+) ATP-ase (SERCA) and IP3 agonist concentrations. Our simulations show that high MT densities observed in the ICC are more relevant to ER establishing Ca(2+) depletion frequencies than protection of the cytosol from elevated free Ca(2+), whereas the SERCA pump is more relevant to containing cytosolic Ca(2+) elevations. Our results further suggest that the level of IP3 agonist stimulating ER Ca(2+) release, subsequent MT uptake, and eventual activation of ER store-operated Ca(2+) entry may determine frequencies of rhythmic pacemaking exhibited by the ICC across species and tissue types.