When is high‐Ca2+ microdomain required for mitochondrial Ca2+ uptake?*

AbstractCa2+ release from IP3‐sensitive stores in the endoplasmic reticulum (ER) induced by Ca2+‐mobilizing agonists generates high‐Ca2+ microdomains between ER vesicles and neighbouring mitochondria. Here we present a model that describes when such microdomains are required and when submicromolar [Ca2+] is sufficient for mitochondrial Ca2+ uptake. Mitochondrial Ca2+ uptake rate in angiotensin II‐stimulated H295R adrenocortical cells correlates with the proximity between ER vesicles and the mitochondrion, reflecting the uptake promoting effect of high‐Ca2+ peri‐mitochondrial microdomains. Silencing or inhibition of p38 mitogen‐activated protein kinase (MAPK) or inhibition of the novel isoforms of protein kinase C enhances mitochondrial Ca2+ uptake and abolishes the positive correlation between Ca2+ uptake and ER‐mitochondrion proximity. Inhibition of protein phosphatases attenuates mitochondrial Ca2+ uptake and also abolishes its positive correlation with ER‐mitochondrion proximity. We postulate that during IP3‐induced Ca2+ release, Ca2+ uptake is confined to ER‐close mitochondria, because of the simultaneous activation of the protein kinases. Attenuation of Ca2+ uptake prevents Ca2+ overload of mitochondria and thus protects the cell against apoptosis. On the other hand, all the mitochondria accumulate Ca2+ at a non‐inhibited rate during physiological Ca2+ influx through the plasma membrane. Membrane potential is higher in ER‐distant mitochondria, providing a bigger driving force for Ca2+ uptake. Our model explains why comparable mitochondrial Ca2+ signals are formed in response to K+ and angiotensin II (equipotent in respect to global cytosolic Ca2+ signals), although only the latter generates high‐Ca2+ microdomains.