Modulation of Ca2+ release and Ca2+ oscillations in HeLa cells and fibroblasts by mitochondrial Ca2+ uniporter stimulation

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Abstract
The recent availability of activators of the mitochondrial Ca2+ uniporter allows direct testing of the influence of mitochondrial Ca2+ uptake on the overall Ca2+ homeostasis of the cell. We show here that activation of mitochondrial Ca2+ uptake by 4,4′,4″‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol (PPT) or kaempferol stimulates histamine‐induced Ca2+ release from the endoplasmic reticulum (ER) and that this effect is enhanced if the mitochondrial Na+–Ca2+ exchanger is simultaneously inhibited with CGP37157. This suggests that both Ca2+ uptake and release from mitochondria control the ability of local Ca2+ microdomains to produce feedback inhibition of inositol 1,4,5‐trisphosphate receptors (InsP3Rs). In addition, the ability of mitochondria to control Ca2+ release from the ER allows them to modulate cytosolic Ca2+ oscillations. In histamine stimulated HeLa cells and human fibroblasts, both PPT and kaempferol initially stimulated and later inhibited oscillations, although kaempferol usually induced a more prolonged period of stimulation. Both compounds were also able to induce the generation of Ca2+ oscillations in previously silent fibroblasts. Our data suggest that cytosolic Ca2+ oscillations are exquisitely sensitive to the rates of mitochondrial Ca2+ uptake and release, which precisely control the size of the local Ca2+ microdomains around InsP3Rs and thus the ability to produce feedback activation or inhibition of Ca2+ release.