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Volume 272, Number 12, Issue of March 21, 1997 pp. 7899-7907
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Submitochondrial Distribution of Three Key Steroidogenic Proteins (Steroidogenic Acute Regulatory Protein and Cytochrome P450_scc and 3-Hydroxysteroid Dehydrogenase Isomerase Enzymes) upon Stimulation by Intracellular Calcium in Adrenal Glomerulosa Cells

(Received for publication, September 18, 1996, and in revised form, December 2, 1996)

Nadia Cherradi ^‡ , Michel F. Rossier ^‡ , Michel B. Vallotton ^‡ , Rina Timberg , Iddo Friedberg , Joseph Orly , Xing Jia Wang ^** , Douglas M. Stocco ^** and Alessandro M. Capponi ^‡

From the ^‡ Division of Endocrinology and Diabetology, Department of Internal Medicine, Faculty of Medicine, University Hospital, CH-1211 Geneva 14, Switzerland, the  Department of Biological Chemistry, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, and the ^** Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430

In adrenal glomerulosa cells, angiotensin II (Ang II) and potassium stimulate aldosterone synthesis through activation of the calcium messenger system. The rate-limiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane. This transfer is believed to depend upon the presence of the steroidogenic acute regulatory (StAR) protein. The aim of this study was 1) to examine the effect of changes in cytosolic free calcium concentration and of Ang II on intramitochondrial cholesterol and 2) to study the distribution of StAR protein in submitochondrial fractions during activation by Ca²⁺ and Ang II. To this end, freshly prepared bovine zona glomerulosa cells were submitted to a high cytosolic Ca²⁺ clamp (600 nM) or stimulated with Ang II (10 nM) for 2 h. Mitochondria were isolated and subfractionated into outer membranes, inner membranes (IM), and contact sites (CS). Stimulation of intact cells with Ca²⁺ or Ang II led to a marked, cycloheximide-sensitive increase in cholesterol in CS (to 143 ± 3.2 and 151.1 ± 18.1% of controls, respectively) and in IM (to 119 ± 5.1 and 124.5 ± 6.5% of controls, respectively). Western blot analysis revealed a cycloheximide-sensitive increase in StAR protein in mitochondrial extracts of Ca²⁺-clamped glomerulosa cells (to 159 ± 23% of controls). In submitochondrial fractions, there was a selective accumulation of StAR protein in IM following stimulation with Ca²⁺ (228 ± 50%). Similarly, Ang II increased StAR protein in IM, and this effect was prevented by cycloheximide. In contrast, neither Ca²⁺ nor Ang II had any effect on the submitochondrial distribution of cytochrome P450_scc and 3-hydroxysteroid dehydrogenase isomerase. The intramitochondrial presence of the latter enzyme was further confirmed by immunogold staining in rat adrenal fasciculata cells and by immunoblot analysis in MA-10 mouse testicular Leydig cells. These findings demonstrate that under acute stimulation with Ca²⁺-mobilizing agents, newly synthesized StAR protein accumulates in IM after transiting through CS. Moreover, our results suggest that the import of StAR protein into IM may be associated with cholesterol transfer, thus promoting precursor supply to the two first enzymes of the steroidogenic cascade within the mitochondria and thereby activating mineralocorticoid synthesis.

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