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Reproductive Biology Lab, Institute of Anatomy II, Heinrich Heine University Duesseldorf, D-40225 Duesseldorf, Germany
Address all correspondence and requests for reprints to: Syed G. Haider, Institute of Anatomy II, Heinrich Heine University, Mooren-Strasse 5, D-40225 Duesseldorf, Germany. E-mail: haider{at}uni-duesseldorf.de.
LH stimulates testosterone synthesis in Leydig cells. On binding with the receptor on the cell membrane of Leydig cell, LH induces the synthesis of cAMP from ATP: cAMP catalyzes the synthesis of protein kinase A, which is needed for the transport of cholesterol from the cytoplasmic pool to mitochondria. Steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR) transfer cholesterol from the outer membrane to the inner mitochondrial membrane (1, 2, 3). Cholesterol transfer, initiated by StAR as the first and rate-limiting step of steroidogenesis, takes place through a gate-like opening created by PBR across the mitochondrial membrane. The enzyme P450 side-chain cleavage (P450scc), residing on the matrix side of the mitochondrial inner membrane, converts cholesterol into pregnenolone, which is ultimately transferred to the smooth endoplasmic reticulum, where testosterone is synthesized by a series of steroidogenic enzymes. LH thus controls the steroid production acutely at the level of StAR and chronically at the level of steroidogenic enzyme gene transcription (for review, see Refs. 4 and 5).
This is a simplified short description of the process of Leydig cell steroidogenesis, and now well established. Two recent publications [Ref. 6 and Midzak et al. in this issue of Endocrinology (7)] show that mitochondria play an additional crucial role in the Leydig cell steroidogenesis. Allen et al. (6) addressed the question of which aspects of mitochondrial function are necessary for acute cAMP-stimulated Leydig cell steroidogenesis by using pharmacological agents known to be mitochondrial disruptors in MA-10 Leydig tumor cells. These authors show that maintenance of mitochondrial membrane potential, mitochondrial ATP synthesis, and mitochondrial pH are all required for acute steroid biosynthesis, leading to the following conclusions: 1) mitochondria must be energized, polarized, and actively respiring to support Leydig cell steroidogenesis, and 2) alterations in the mitochondrial state may thus be involved in regulating steroid biosynthesis.
These results inspired Midzak et al. (7) to explore steroidogenesis and mitochondrial function in primary cultures of freshly isolated Brown Norway rat Leydig cells using the mitochondrial toxin myxothiazol (MYX) to disrupt the electron transport chain. MYX lowers oxygen consumption of the cells by blocking transport of electrons through cytochrome b-c1 of mitochondrial complex III and is therefore widely accepted as a specific inhibitor of mitochondrial complex III. The principal findings of Midzak et al. are: 1) MYX profoundly inhibits the LH-stimulated testosterone production, as a function of concentration; 2) MYX inhibits LH-stimulated testosterone production at multiple sites along the steroidogenic pathway (3ß-hydroxysteroid dehydrogenase, P450c17, and 17ß-hydroxysteroid dehydrogenase); and 3) MYX plus LH significantly reduce the intracellular content of ATP. These three findings were expected and confirmed the classical hormone-mediated mechanism of steroidogenesis.
And now the unexpected observations: 1) the basal (unstimulated) testosterone production increases significantly from control in response to MYX concentrations; 2) MYX increases basal testosterone production by a mechanism other than enhancement of StAR-dependent cholesterol transport; 3) increased basal testosterone production by MYX is not a result of reduced testosterone metabolism; and 4) five mitochondrial inhibitors for respiratory chain complexes I, II, and III are as effective in stimulating basal testosterone production as MYX.
The authors provide convincing data to support the contention that the MYX effects on testosterone reflect its inhibitory effects on mitochondrial electron transport chain. The mechanism of increased basal testosterone production by MYX, which occurs within minutes and thus nongenomic, is currently unclear. Midzak et al. (7) performed an additional experiment to explain their surprising finding, and showed that the intracellular calcium chelator BAPTA-AM suppressed MYX-mediated steroidogenesis but had no effect on basal or hydroxycholesterol-mediated steroidogenesis, evidence for a positive calcium-mediated mechanism of MYX.
Why calcium? Mitochondria accumulate calcium and regulate intracellular calcium levels (8): inhibition of the electron transport chain increases intracellular calcium levels. Increased calcium levels result in an increase in stimulated Leydig cell testosterone production, whereas suppression of calcium increase by chelation suppresses steroid synthesis (9, 10, 11). An alternative explanation for MYX-mediated effects on steroidogenesis, as discussed by Midzak et al. (7), is through PBR stimulation at the mitochondrial membrane. PBR is involved in the regulation of mitochondrial membrane potential and in cellular oxygen sensing: two processes strongly dependent on the electron transport chain (12): change in the redox status of the Leydig cell has been shown to modify PBR and its ability to transport cholesterol.
The importance of mitochondria for a classical hormone-mediated steroidogenesis is well known. Thanks to the papers of Allen et al. (6) and Midzak et al. (7), we are starting to learn a crucial regulatory function of mitochondria in steroidogenesis. Is this function other than via classical hormonal systems? The data of Midzak et al. (7) promise a point of departure for further research to explore the physiological aspects of this process.
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Disclosure Statement: The author has nothing to disclose.
Received March 9, 2007.
Accepted for publication March 23, 2007.
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