Mitochondrial cAMP and Ca²⁺ metabolism in adrenocortical cells

The biological effects of physiological stimuli of adrenocortical glomerulosa cells are predominantly mediated by the Ca²⁺ and the cAMP signal transduction pathways. The complex interplay between these signalling systems fine-tunes aldosterone secretion. In addition to the well-known cytosolic interactions, a novel intramitochondrial Ca²⁺-cAMP interplay has been recently recognised. The cytosolic Ca²⁺ signal is rapidly transferred into the mitochondrial matrix where it activates Ca²⁺-sensitive dehydrogenases, thus enhancing the formation of NADPH, a cofactor of steroid synthesis. Quite a few cell types, including H295R adrenocortical cells, express the soluble adenylyl cyclase within the mitochondria and the elevation of mitochondrial [Ca²⁺] activates the enzyme, thus resulting in the Ca²⁺-dependent formation of cAMP within the mitochondrial matrix. On the other hand, mitochondrial cAMP (mt-cAMP) potentiates the transfer of cytosolic Ca²⁺ into the mitochondrial matrix. This cAMP-mediated positive feedback control of mitochondrial Ca²⁺ uptake may facilitate the rapid hormonal response to emergency situations since knockdown of soluble adenylyl cyclase attenuates aldosterone production whereas overexpression of the enzyme facilitates steroidogenesis in vitro. Moreover, the mitochondrial Ca²⁺-mt-cAMP-Ca²⁺ uptake feedback loop is not a unique feature of adrenocortical cells; a similar signalling system has been described in HeLa cells as well.