Functional TASK-3–Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells

Abstract

Ca2+ drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa (ZG) cell. Membrane potential across each of these compartments regulates the amplitude of the Ca2+ signal; yet, only plasma membrane ion channels and their role in regulating cell membrane potential have garnered investigative attention as pathological causes of human hyperaldosteronism. Previously, we reported that genetic deletion of TASK-3 channels from mice produces aldosterone excess in the absence of a change in the cell membrane potential of ZG cells. Here, we report using yeast two-hybrid, immunoprecipitation and electron microscopic analyses that TASK-3 channels are resident in mitochondria, where they regulate mitochondrial morphology, mitochondrial membrane potential (mitoVm) and aldosterone production. This study provides proof-of-principle that mitochondrial K+ channels, by modulating inner mitochondrial membrane morphology and mitoVm, have the ability to play a pathological role in aldosterone dysregulation in steroidogenic cells.

Of Mice and Man and the Regulation of Aldosterone Secretion

“…The current studies by Yao et al 1 raise the possibility that rapid changes in the mitochondrial membrane potential mediated by A-II or K + lead to an increase in the efficiency of CYP11B2 synthesis of aldosterone. As a corollary, dysregulation of the mitochondrial membrane potential may be involved in the genesis of autonomous aldosterone production in PA.…”

“…As a corollary, dysregulation of the mitochondrial membrane potential may be involved in the genesis of autonomous aldosterone production in PA. The TASK-3 antagonist, C23, stimulated aldosterone secretion in the human adrenocortical carcinoma cell H295R modestly even in cells stimulated by A-II, however the modest stimulation may be due to the very low expression of TASK 3 in the H295R cells 1 .…”

“…The new findings by Yao et al 1 bring up another issue that has been ignored since the kinetics of CYP11B2 was first described and confirmed. CYP11B2 is a relatively inefficient partial processing enzyme which successively hydroxylates DOC to corticosterone, 18-hydroxycorticosterone, and then aldosterone.…”

“…Despite the importance of PA in cardiovascular and renal disease, its pathogenesis is only partially clarified in aldosterone-producing adenomas and remains unknown in idiopathic hyperaldosteronism. A report in this issue by Yao et al 1 provides crucial new information on the normal control of aldosterone synthesis that could elucidate mechanisms for its dysregulation in PA. They used elegant technology to demonstrate that TASK-3 K + channels locates in the mitochondria and interact with proteins of the electron transport chain of the mitochondrial inner membrane and regulate mitochondrial membrane potential and morphology.…”

“…Yao et al show that mitochondria not only express the K + selective channels mito KATP (K -ir 6.1/6.2), mito BK Ca (slo 1) and mito Kv1.3, but also TASK-3, that reduce mitochondrial membrane potential and Ca ++ uptake, and thus protecting the cell from apoptosis 1 , and also abrogating the stimulus for aldosterone synthesis. The current studies by Yao et al 1 raise the possibility that rapid changes in the mitochondrial membrane potential mediated by A-II or K + lead to an increase in the efficiency of CYP11B2 synthesis of aldosterone.…”