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P2 Calcium Induced Intramitochondrial cAMP Signalling Enhances Aldosterone Secretion


Elevation of plasma [K+] and [angiotensin II] (Ang II), two major physiological stimuli of adrenal zona glomerulosa cells, increase aldosterone production by triggering cytosolic Ca2+ signalling. Cytosolic Ca2+ signals are accompanied by mitochondrial Ca2+ elevations which further strengthen this steroidogenic response. It has recently been recognized that such mitochondrial Ca2+ signals activate the mitochondrial soluble adenylyl cyclase (sAC) thus evoking intramitochondrial (matrix) cAMP elevations during Ca2+ signalling. We hypothesised that this Ca2+ induced mitochondrial cAMP production, too, contributes to the hypersecretion of aldosterone. Using human adrenocortical H295R cells we found that silencing of sAC decreased mitochondrial cAMP production and, at the same time, decelerated Ca2+ accumulation by the organelle. On the other hand, inhibition of the mitochondrial phosphodiesterase (PDE2A) intensified matrix cAMP production and accelerated mitochondrial Ca2+ uptake. More importantly, both pharmacological inhibition and knock-down of sAC mitigate AngII-induced aldosterone production. Finally, overexpression of wild-type sAC within the mitochondrial matrix increased mitochondrial cAMP formation, accelerated mitochondrial Ca2+ uptake and, most prominently, potentiated aldosterone production as compared to the enzymatically inactive mutant enzyme. Altogether, Ca2+-induced mitochondrial cAMP signalling supports aldosterone production by favouring additional Ca2+ influx into the organelle. This positive feed-back loop may expedite the hormonal response when immediate hypersecretion of mineralocorticoids is crucial for cardiovascular compensation (e.g. exsiccation, blood loss).


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Correspondence to Gergő Szanda.

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Szanda, G., Wisniewski, É., Rajki, A. et al. P2 Calcium Induced Intramitochondrial cAMP Signalling Enhances Aldosterone Secretion. Artery Res 25 (Suppl 1), S44 (2019).

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