title: Alteration in accumulated aldosterone synthesis as a result of N-terminal cleavage of aldosterone synthase.
abstract: 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.
authors.affiliation: Department of Biochemistry, Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Savannah, GA 31404, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Adams
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis*; D002460:Cell Line; D002474:Cell-Free System; D019405:Cytochrome P-450 CYP11B2 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D059748:Proteolysis
chemical_list: D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2