Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization

We investigated the consequences of depolarizing the mitochondrial membrane potential (Delta psi(mit)) on Ca2+ signals arising via inositol 1,4,5-trisphosphate receptors (InsP(3)R) in hormone-stimulated HeLa cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or a mixture of antimycin A(+) oligomycin were found to rapidly depolarize Delta psi(mit). Mitochondrial depolarization enhanced the number of cells responding to a brief application of a Ca2+-mobilizing hormone and prolonged the recovery of cytosolic Ca2+ after washout of the hormone; effects consistent with the removal of a passive Ca2+ buffer. However, with repeated application of the same hormone concentration both the number of responsive cells and peak Ca2+ changes were observed to progressively decline. The inhibition of Ca2+ signalling was observed using different Ca2+ mobilizing hormones and also with a membrane-permeant Ins(1,4,5)P-3 eater. Upon washout of FCCP, the Ca2+ signals recovered with a time course similar to the re-establishment of Delta psi(mit). Global measurements indicated that none of the obvious factors such as changes in pH, ATP concentration, cellular redox state, permeability transition pore activation or reduction in Ca2+-store loading appeared to underlie the inhibition of Ca2+ signalling. We therefore suggest that local changes in one or more of these factors, as a consequence of depolarizing Delta psi(mit), prevents InsP(3)R activation.