Introduction. Steroidogenesis, StAR and PBR: Is There Light at the End of the Tunnel?

The biochemistry and physiology of steroidogenesis have been active areas of investigation for more than 30 years. Once the techniques of molecular biology were applied to this effort, the understanding of the regulation of steroidogenesis and the steroidogenic enzymes themselves moved forward at a rapid pace. While steroidogenesis is crucial for development and homeostasis in all animal species, the pattern of steroid hormone expression between different species is quite variable. However all steroidogenic pathways in all species begin in the mitochondrion with the conversion of cholesterol to pregnenolone. A mitochondrial steroid hydroxylase, cholesterol side-chain cleavage cytochrome P-450 (P-450scc), located in the inner mitochondrial membrane catalyzes this reaction. P-450scc activity is supported by a mini-electron transport chain located in the mitochondrial matrix, and it is presumed that P-450scc is an integral protein of the inner mitochondrial membrane that faces the matrix. In addition to being a substrate for steroidogenesis, cholesterol is a component of membranes. Presumably the inner mitochondrial membrane in the steroidogenic factories (adrenal cortex, Leydig cells in testis, thecal and granulosa cells in ovary) contain two pools of cholesterol; one for maintenance of membrane structure, which is found in inner mitochondrial membranes in all tissues, and a steroidogenic pool found exclusively or most abundantly in the above tissues. Cholesterol is one of the most hydrophobic lipids, and its conversion to the more polar pregnenolone occurs very rapidly in steroidogenic cells in response to stimulus by peptide hormones from the anterior pituitary (ACTH, LH, FSH). It has long been a mystery how steroidogenic cholesterol is transported rapidly from lipid stores or the site of de novo synthesis to the mitochondrion and then across the double membranes of the mitochondrion to the vicinity of P-450scc.