Intramitochondrial Cholesterol Transfer in Steroidogenic Cells

Abstract

The acute biosynthesis of steroid hormones in response to trophic hormone stimulation is controlled by transferring substrate cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane where it is converted into pregnenolone, the first steroid synthesized, by the cytochorme P450 side chain cleavage enzyme system. This regulation is cycloheximide sensitive and thus requires a protein factor whose role it is to mediate this transfer of cholesterol. One candidate for the regulatory protein is the mitochondrial phosphoprotein, the steroidogenic acute regulatory (StAR) protein. Cloning and sequencing of the StAR cDNA indicated that it was a novel protein. Transient transfections with the cDNA for the StAR protein resulted in increased steroid production in both MA-10 and COS-1 cells in the absence of stimulation. Mutations in the StAR gene have been shown to cause the potentially lethal disease, congenital lipoid adrenal hyperplasia, a condition in which cholesterol transfer to the P450scc is blocked. Recently, a protein with homology to a region in the C-terminal portion of the StAR protein has been cloned and shown to display some cholesterol transferring capacity. While it appears that StAR is the acute regulator of steroid biosynthesis, the mechanism which results in cholesterol transfer to the inner mitochondrial membrane is still unknown.