Signal Transduction of Steroidogenic Hormones to the Adrenal and Gonadal Mitochondria and the Possibilities for Combating Lipoid Congenital Adrenal Hyperplasia

In steroidogenic tissue the first and rate limiting step of steroid hormone synthesis is the transport of cholesterol from the outer mitochondrial membrane to the inner membrane where it is enzymatically converted by cytochrome P450 side chain cleavage (P450scc) to pregnenolone, which is the metabolic precursor for all steroid hormones. This step is accelerated by steroidogenic hormones but how the signal from the periphery is transmitted to the mitochondria is only partially established. The steroidogenic acute regulatory protein (StAR) is known to accelerate the export of cholesterol from the outer mitochondrial membrane. StAR may bind cholesterol in its hydrophobic pocket and then transport or propel cholesterol towards the inner membrane. This action is thought to be dependent on interaction with proteins in the contact sites between the inner and outer mitochondrial membranes, such as the translocator protein and the voltage-dependent anion channel. Mutations in StAR often rob the protein of its steroidogenic properties and result in lipoid congenital adrenal hyperplasia (LCAH), a condition that is characterized by a build up of cholesterol and cholesterol esters in steroidogenic cells, deficiencies in mineralocorticoids and glucocorticoids and XY genetic males with female phenotypic external genitalia. StAR expression in healthy individuals is known to be regulated by protein kinase A and the transcription factor Nurr77. A complete understanding the workings of the signal transduction machinery in steroidogenic cells may allow future plans to combat LCAH by using gene therapy to restore appropriate activity to StAR gene products.