Optimal microdomain crosstalk between endoplasmic reticulum and mitochondria for Ca2+ oscillations

A Ca2+ signaling model is proposed to consider the crosstalk of Ca2+ ions between endoplasmic reticulum (ER) and mitochondria within microdomains around inositol 1, 4, 5-trisphosphate receptors (IP3R) and the mitochondrial Ca2+ uniporter (MCU). Our model predicts that there is a critical IP3R-MCU distance at which 50% of the ER-released Ca2+ is taken up by mitochondria and that mitochondria modulate Ca2+ signals differently when outside of this critical distance. This study highlights the importance of the IP3R-MCU distance on Ca2+ signaling dynamics. The model predicts that when MCU are too closely associated with IP(3)Rs, the enhanced mitochondrial Ca2+ uptake will produce an increase of cytosolic Ca2+ spike amplitude. Notably, the model demonstrates the existence of an optimal IP3R-MCU distance (30-85 nm) for effective Ca2+ transfer and the successful generation of Ca2+ signals in healthy cells. We suggest that the space between the inner and outer mitochondria membranes provides a defense mechanism against occurrences of high [Ca2+](Cyt). Our results also hint at a possible pathological mechanism in which abnormally high [Ca2+](Cyt) arises when the IP3R-MCU distance is in excess of the optimal range.