The recent availability of mitochondrial Ca²⁺ uniporter activators allows testing directly the influence of mitochondrial Ca²⁺ uptake on the overall cell Ca²⁺ homeostasis. We have used here two of these activators, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and the flavonoid kaempferol, which have a completely different chemical structure, to investigate the effects of mitochondrial Ca²⁺ uptake on Ca ²⁺ release from the endoplasmic reticulum and Ca²⁺ oscillations.

Both compounds stimulated histamine-induced Ca²⁺ release from the endoplasmic reticulum and this effect was enhanced if the mitochondrial Na⁺/ Ca²⁺ exchanger was simultaneously inhibited with CGP37157. This suggests that both Ca²⁺ uptake and release from mitochondria control the ability of local Ca²⁺ microdomains to produce feed-back inhibition of inositol 1,4,5-trisphosphate receptors. In addition, the ability of mitochondria to control Ca²⁺ release from the endoplasmic reticulum 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 fibroblasts previously silent. 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 inositol 1,4,5-trisphosphate receptors and thus its ability to produce feedback activation or inhibition of Ca²⁺ release.