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This version published online on May 11, 2006
Endocrinology, doi:10.1210/en.2005-1204
A more recent version of this article appeared on August 1, 2006
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*Compound via MeSH
*Substance via MeSH

Submitted on September 20, 2005
Accepted on May 3, 2006

ENERGIZED, POLARIZED AND ACTIVELY RESPIRING MITOCHONDRIA ARE REQUIRED FOR ACUTE LEYDIG CELL STEROIDOGENESIS

John A. Allen, Tristan Shankara, Paul Janus, Steve Buck, Thorsten Diemer, Karen Held Hales, and Dale B. Hales*

Departments of Physiology and Biophysics and Bioengineering, University of Illinois at Chicago, Chicago, Illinois and Department of Urology, University Hospital of the Justus-Liebig University, Giessen, Germany

* To whom correspondence should be addressed. E-mail: dbhale{at}uic.edu.

The first and rate limiting step in the biosynthesis of steroid hormones is the transfer of cholesterol into mitochondria, which is facilitated by the steroidogenic acute regulatory (StAR) protein. Recent study of Leydig cell function has focused on the mechanisms regulating steroidogenesis, however few investigations have examined the importance of mitochondria in this process. The purpose of this investigation was to determine which aspects of mitochondrial function are necessary for acute cAMP-stimulated Leydig cell steroidogenesis. MA-10 cells were treated with 8-bromo-cAMP (cAMP) and different site specific agents which disrupt mitochondrial function, and the effects on acute cAMP-stimulated progesterone synthesis, StAR mRNA and protein, mitochondrial membrane potential ({Delta}{psi}m) and ATP synthesis were determined. cAMP treatment of MA-10 cells resulted in significant increases in both cellular respiration and {Delta}{psi}m. Dissipating {Delta}{psi}m with carbonyl cyanide m-chlorophenyl hydrazone resulted in a profound reduction in progesterone synthesis, even in the presence of newly synthesized StAR protein. Preventing electron transport in mitochondria with antimycin A significantly reduced cellular ATP, potently inhibited steroidogenesis, and reduced StAR protein levels. Inhibiting mitochondrial ATP synthesis with oligomycin reduced cellular ATP, inhibited progesterone synthesis and StAR protein, but had no effect on {Delta}{psi}m. Disruption of intramitochondrial pH ({Delta}pH) with nigericin significantly reduced progesterone production and StAR protein but had minimal effects on {Delta}{psi}m. 22(R)-Hydroxycholesterol-stimulated progesterone synthesis was not inhibited by any of the mitochondrial reagents, indicating that neither P450scc nor 3{beta}-HSD activity were inhibited. These results indicate that {Delta}{psi}m, mitochondrial ATP synthesis, and mitochondrial pH are all required for acute steroid biosynthesis. These results suggest that mitochondria must be energized, polarized and actively respiring to support Leydig cell steroidogenesis and alterations in the state of mitochondria may be involved in regulating steroid biosynthesis.




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