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

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. In either location, 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]. However, the HSD activity found in the mitochondrial fraction was attributed to microsomal contamination and the result of the homogenizion process. While this study established the legitimacy of microsomal HSD, it tended to preclude further research on mitochondrial HSD. For mitochondrial HSD to be considered a distinct and separate entity, additional research over a number of years would be required. Starting in 1965, investigators began to report a dual location for HSD in ovaries [2-4], testes [5,6], human term placenta [7-10], and rat adrenal cortex [11-14]. In toto, these studies suggested that mitochondrial HSD was indeed a separate entity. Other investigators, however, still considered mitochondrial HSD activity to be due to microsomal contamination [15,16], and the result of a redistribution artifact [17].In 1979, we reported the results of an intracellular enzyme distribution study of HSD, cytochrome c oxidase (mitochondrial marker), and steroid 21 hydroxylase (microsomal marker) in rat adrenal cortex [18]. We found that exhaustively washed mitochondria retained 26 % of total HSD activity. In retrospect, this percentage appears to be on the low side. For example, when the specific activity of microsomal HSD is d