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.
Footnotes
This work was supported by the National Institutes of Health [Grant HD057876] and the Anderson Cancer Institute (H.S.B.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- AS
- aldosterone synthase
- DOC
- deoxycorticosterone
- SCC
- cytochrome P450 side-chain cleavage enzyme
- ANGII
- angiotensin II
- MPP
- mitochondrial processing peptidase
- IMS
- intermembrane space
- CFS
- cell-free transcription/translation
- RIA
- radioimmunoassay
- OMM
- outer mitochondrial membrane
- MPP
- mitochondrial processing peptidase
- IMM
- inner mitochondrial membrane
- COXIV
- cytochrome c oxidase subunit IV
- DHFR
- dihydrofolate reductase
- Hsp70
- heat shock protein 70
- Tim
- translocase inner membrane
- Tom
- translocase outer membrane.
- Received October 19, 2011.
- Accepted December 19, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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