Yao Junlan, McHedlishvili David, McIntire William E, Guagliardo Nick A, Erisir Alev, Coburn Craig A, Santarelli Vincent P, Bayliss Douglas A, Barrett Paula Q
From the Departments of Pharmacology (J.Y., D.M., W.E.M., N.A.G., D.A.B., P.Q.B.) and Psychology (A.E.), University of Virginia School of Medicine, Charlottesville; Silverback Therapeutics, Inc, Seattle, WA (C.A.C.); and Department of Neuroscience, Merck & Co, Inc, West point, PA (V.P.S.).
Hypertension. 2017 Aug;70(2):347-356. doi: 10.1161/HYPERTENSIONAHA.116.08871. Epub 2017 Jun 19.
Ca drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa cell. Membrane potential across each of these compartments regulates the amplitude of the Ca 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 (tandem pore domain acid-sensitive K channels) from mice produces aldosterone excess in the absence of a change in the cell membrane potential of zona glomerulosa cells. Here, we report using yeast 2-hybrid, immunoprecipitation, and electron microscopic analyses that TASK-3 channels are resident in mitochondria, where they regulate mitochondrial morphology, mitochondrial membrane potential, and aldosterone production. This study provides proof of principle that mitochondrial K channels, by modulating inner mitochondrial membrane morphology and mitochondrial membrane potential, have the ability to play a pathological role in aldosterone dysregulation in steroidogenic cells.
钙离子在肾上腺球状带细胞的胞质溶胶和线粒体区室中驱动醛固酮的合成。这些区室中每个区室的膜电位调节钙离子信号的幅度；然而，作为人类醛固酮增多症的病理原因，只有质膜离子通道及其在调节细胞膜电位中的作用受到了研究关注。此前，我们报道从小鼠中基因删除TASK-3通道（串联孔结构域酸敏感钾通道）在球状带细胞膜电位无变化的情况下会产生醛固酮过量。在此，我们报告使用酵母双杂交、免疫沉淀和电子显微镜分析表明，TASK-3通道定位于线粒体中，在那里它们调节线粒体形态、线粒体膜电位和醛固酮生成。这项研究提供了原理证明，即线粒体钾通道通过调节线粒体内膜形态和线粒体膜电位，有能力在类固醇生成细胞的醛固酮失调中发挥病理作用。
