The salt-water balance of the body is primarily regulated by aldosterone, whose synthesis and secretion are under the control of cytosolic and mitochondrial Ca2+, as well as cAMP. In the mitochondrial matrix, soluble adenylyl cyclase (sAC) generates mitochondrial cAMP (mt-cAMP), and mt-cAMP production is enhanced by mitochondrial Ca2+. Since a decrease in sAC leads to reduced mt-cAMP and less aldosterone production, András Spät, Gergő Szanda and colleagues (Szanda et al., 2018) test in their Research Article whether this effect of mt-cAMP on steroids also affects mitochondrial Ca2+ signalling. The authors show that elevated cytosolic Ca2+ resulted in mitochondrial Ca2+ uptake and mt-cAMP production that is based on sAC, whereas lowering mt-cAMP production decelerated the uptake of Ca2+ into mitochondria. Thus, the mitochondrial Ca2+ signal evokes a positive feedback loop through sAC and mt-cAMP to enhance further Ca2+ uptake into the organelle, and this supports steroid synthesis. Importantly, this signalling is mediated by the guanine exchange factor for RAP GTPase Epac1, which is activated by mt-cAMP. Furthermore, this feedback control is not restricted to steroid-producing cells. This study thereby uncovers a physiological convergence mechanism for mitochondrial Ca2+ uptake and cAMP signalling to support steroid synthesis.
