Department of Biochemistry, Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Savannah, GA 31404, USA.
Mol Pharmacol. 2012 Mar;81(3):465-74. doi: 10.1124/mol.111.076471. Epub 2011 Dec 19.
Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, which takes 12 h to reach full effect, and then 24 h to subside. However, this promoter-dependent regulation of aldosterone production fails to explain phenomena such as rapid-onset hypertension that occurs quickly and then subsides. Here, we investigate the fate of AS after expression and how these events relate to aldosterone production. Using isolated mitochondria from steroidogenic cells and cell-free synthesized AS, we first showed that the precursor form of AS translocated into the matrix of the mitochondria, where it underwent cleavage by mitochondrial processing peptidase to a mature form approximately 54 kDa in size. Mature AS seemed to translocate across the inner mitochondrial membrane a second time to finally reside in the intermembrane space. Unprocessed N-terminal AS has 2-fold more activity than physiological levels. These results show how the subcellular mechanisms of AS localization relate to production of aldosterone and reveal a rapid, promoter-independent regulation of aldosterone production.
醛固酮合酶 (AS) 通过合成盐皮质激素醛固酮来调节血量。肾上腺中醛固酮的过度产生会导致高血压，这是心脏病和中风的主要原因。醛固酮的产生取决于肾素-血管紧张素系统对 AS 表达的刺激，这需要 12 小时才能达到完全效果，然后需要 24 小时才能消退。然而，这种依赖启动子的醛固酮产生调节不能解释快速发作性高血压等现象，这种高血压会迅速发生然后消退。在这里，我们研究了 AS 表达后的命运以及这些事件与醛固酮产生的关系。使用来自于类固醇生成细胞的分离线粒体和无细胞合成的 AS，我们首先表明，AS 的前体形式易位进入线粒体的基质中，在那里它被线粒体加工肽切割成大约 54 kDa 大小的成熟形式。成熟的 AS 似乎第二次穿过线粒体内膜，最终驻留在膜间空间。未加工的 N 端 AS 的活性比生理水平高 2 倍。这些结果表明 AS 定位的亚细胞机制与醛固酮的产生有关，并揭示了醛固酮产生的快速、启动子独立的调节。
