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-tris phosphate receptors (InsP(3)R) in hormone-stimulated HeLa cells. Carbonyl c yanide p-trifluoromethoxyphenylhydrazone (FCCP) or a mixture of antimycin A (+) oligomycin were found to rapidly depolarize Delta psi(mit). Mitochondri al depolarization enhanced the number of cells responding to a brief applic ation 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 hormon e concentration both the number of responsive cells and peak Ca2+ changes w ere observed to progressively decline. The inhibition of Ca2+ signalling wa s observed using different Ca2+ mobilizing hormones and also with a membran e-permeant Ins(1,4,5)P-3 eater. Upon washout of FCCP, the Ca2+ signals reco vered with a time course similar to the re-establishment of Delta psi(mit). Global measurements indicated that none of the obvious factors such as cha nges in pH, ATP concentration, cellular redox state, permeability transitio n pore activation or reduction in Ca2+-store loading appeared to underlie t he inhibition of Ca2+ signalling. We therefore suggest that local changes i n one or more of these factors, as a consequence of depolarizing Delta psi( mit), prevents InsP(3)R activation.