RT Journal Article SR Electronic T1 Alteration in Accumulated Aldosterone Due to N-terminal Cleavage of Aldosterone Synthase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.111.076471 DO 10.1124/mol.111.076471 A1 Brian P Adams A1 Himangshu S Bose YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/12/19/mol.111.076471.abstract AB Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralo-corticoid, 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 hours to reach full effect, and then 24 hours to subside. However, this promoter-dependant 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 appeared to translocate across the inner mitochondrial membrane a second time to finally reside in the intermembrane space. Unprocessed N-terminal AS has two-fold more activity than physiological levels. These results show how the sub-cellular mechanisms of AS localization relate to production of aldosterone, and reveal a rapid, promoter independent regulation of aldosterone production.