Transduction of acth signal from plasma membrane to mitochondria in adrenocortical steroidogenesis. Effects of peptide, phospholipid, and calcium

The conversion of cholesterol to pregnenolone by adrenocortical mitochondria is the rate-limiting step in steroidogenesis. This process is stimulated dramatically by the action of ACTH through the sequential reactions, in which adenyl cyclase, cAMP-dependent protein kinase, cholesterol esterase and ribosomal protein synthesis are all involved. The de novo synthesized protein, the so-called labile protein with a half-life of approx 10 min, is believed to stimulate the cholesterol side chain cleavage reaction by an unknown mechanism. Available evidence indicates that the electron transfer reaction from NADPH to P-450 scc is mediated rapidly by adrenodoxin reductase and p-450 scc. In addition, these redox components are inactivated slowly with a half-life of 3.5 days after hypophysectomy. It is known that the corticoid output from adrenocortical cells starts within 5 min and reaches the maximum after 10–15 min of ACTH administration to animals. One can assume that under normal physiological conditions, both O 2 and NADPH are not limiting. Additionally, mitochondrial inner membranes are poor in cholesterol. In this context, the availability of substrate cholesterol to P-450 sccis the most likely candidate for the regulatory mechanism.