Mitochondria suppress local feedback activation of inositol 1,4,5-trisphosphate receptors by Ca2+

The concerted action of inositol 1,4,5-trisphosphate (IP3) and Ca2+ on the IP3 receptor Ca2+ release channel (IP3R) is a fundamental step in the gener ation of cytosolic Ca2+ oscillations and waves, which underlie Ca2+ signali ng in many cells. Mitochondria appear in close association with regions of endoplasmic reticulum (ER) enriched in IP3R and are particularly responsive to IP3-induced increases of cytosolic Ca2+ ([Ca2+](c)). To determine wheth er feedback regulation of the IP3R by released Ca2+ is modulated by mitocho ndrial Ca2+ uptake, the interactions between ER and mitochondrial Ca2+ pool s were examined by fluorescence imaging of compartmentalized Ca2+ indicator s in permeabilized hepatocytes, IP3 decreased luminal ER Ca2+ ([Ca2+](ER)), and this was paralleled by an increase in mitochondrial matrix Ca2+ ([Ca2](m)) and activation of Ca2+-sensitive mitochondrial metabolism. Remarkably , the decrease in [Ca2+](ER) evoked by submaximal IP3 was enhanced when mit ochondrial Ca2+ uptake was blocked with ruthenium red or uncoupler. Moreove r, subcellular regions that were relatively deficient in mitochondria demon strated greater sensitivity to IP3 than regions of the cell with a high den sity of mitochondria. These data demonstrate that Ca2+ uptake by the mitoch ondria suppresses the local positive feedback effects of Ca2+ on the IP3R, giving rise to subcellular heterogeneity in IP3 sensitivity and IP3R excita bility. Thus, mitochondria can play an important role in setting the thresh old for activation and establishing the subcellular pattern of IP3-dependen t [Ca2+](c) signaling.