Calcium buffering activity of mitochondria controls basal growth hormone secretion and modulates specific neuropeptide signaling

Goldfish somatotropes contain multiple functionally distinct classes of non-mitochondrial intracellular Ca2+ stores. In this study, we investigated the role of mitochondrial Ca2+ handling in the control of hormone secretion. Inhibition of mitochondrial Ca2+ uptake with 10 μM ruthenium red (RR) and 10 μM carbonyl cyanide m-chlorophenylhydrazone (CCCP) caused a small and reversible increase in cytosolic [Ca2+]. Despite relatively modest global Ca2+ signals, RR and CCCP stimulated robust GH secretion under basal culture conditions. CCCP-stimulated hormone release was abolished in cells pre-incubated with 50 μM BAPTA-AM, suggesting that elevations in cytosolic [Ca2+] mediate this release of GH. Both caffeine-sensitive intracellular Ca2+ stores and l-type Ca2+ channels can be the source of the Ca2+ buffered by mitochondria in somatotropes. The stimulatory effect of RR on caffeine-stimulated GH release was enhanced dramatically in the presence of ryanodine, pointing to a complex interaction between these three Ca2+ stores. Inhibition of mitochondrial Ca2+ uptake with RR augmented GH release evoked by only one of the two endogenous gonadotropin-releasing hormones. Thus, we provide the first evidence that mitochondrial Ca2+ buffering is differentially involved in specific agonist Ca2+ signaling pathways and plays an important role in the control of basal GH release.