Mitochondrial 3 beta-hydroxysteroid dehydrogenase (HSD) is essential for the synthesis of progesterone by corpora lutea: An hypothesis

John C Chapman,Sandra D Michael,Soohong Min,Jose R Polanco

doi:10.1186/1477-7827-3-11

John C Chapman, Sandra D Michael + Show 2 more

Open Access

https://doi.org/10.1186/1477-7827-3-11

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Abstract

In mouse ovaries, the enzyme 3 beta-hydroxysteroid dehydrogenase (HSD) is distributed between microsomes and mitochondria. Throughout the follicular phase of the estrous cycle, the HSD activity in microsomes is predominant; whereas, after LH stimulation, HSD activity during the luteal phase is highest in the mitochondria. The current study examined whether or not LH stimulation always results in an increase in mitochondrial HSD activity. This was accomplished by measuring the HSD activity in microsomal and mitochondrial fractions from ovaries of pregnant mice. These animals have two peaks of LH during gestation, and one peak of LH after parturition. It was found that mitochondrial HSD activity was highest after each peak of LH. It is proposed that mitochondrial HSD is essential for the synthesis of high levels of progesterone. The increase in HSD activity in mitochondria after LH stimulation occurs because: 1) LH initiates the simultaneous synthesis of HSD and the cholesterol side-chain cleavage enzyme (P450scc); and, 2) HSD and P450scc bind together to form a complex, which becomes inserted into the inner membrane of the mitochondria. High levels of progesterone are synthesized by mitochondrial HSD because: 1) the requisite NAD+ cofactor for progesterone synthesis is provided directly by the mitochondria, rather than indirectly via the rate limiting malate-aspartate shuttle; and, 2) the end-product inhibition of P450scc by pregnenolone is eliminated because pregnenolone is converted to progesterone.

Highlights

With the exception of 3β-hydroxysteroid dehydrogenase (HSD), the enzymes involved in the conversion of cholesterol to steroid hormones are located in either the mitochondria or the endoplasmic reticulum
The present study examined the distribution of HSD activity in pregnant mouse ovaries to determine whether or not mitochondrial HSD activity increased after each peak of LH
One level occurs during the follicular phase, and a higher level of synthesis occurs throughout the luteal phase

Summary

Introduction

With the exception of 3β-hydroxysteroid dehydrogenase (HSD), the enzymes involved in the conversion of cholesterol to steroid hormones are located in either the mitochondria or the endoplasmic reticulum. HSD is unique in that it is located in both subcellular organelles. HSD converts pregnenolone and dehydroepiandosterone (DHEA) to progesterone and androstenedione, respectively, using NAD+ as cofactor. The reason for two separate sites for this enzyme is not known. Establishing the existence of two separate locations for HSD has been a lengthy process. In 1956, Beyer and Samuels reported that the microsomal (endoplasmic reticulum) and mitochondrial fractions from the homogenate of bovine adrenal cortex contained HSD activity [1]

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