High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex

The adrenal cortex is a tissue of excess in terms of both cholesterol metabolism and cholesterol exchange with the circulation. Exceptionally high levels of lipoprotein receptors in this highly vascularized tissue provide ready access to dietary cholesterol, allowing the adrenocortical cells to maintain impressive stores of cytoplasmic cholesterol ester (CE) droplets. Tightly packed among the CE droplets are specialized mitochondria, carrying in their inner membranes high levels of the cytochrome P450scc (CYP11A1). This enzyme carries out the so-called side chain cleavage reaction, consuming cholesterol to produce pregnenolone, the precursor of cortisol and all other steroids. Glucocorticoid synthesis is tightly regulated at the level of cholesterol metabolism, which responds to ACTH stimulation over a period of minutes and ceases equally quickly when this hormone is removed. Remarkably, this dynamic process is modulated under most circumstances not by control of the intrinsic enzymatic activity of P450scc, but rather by substrate availability. For this reason, cholesterol transport within the mitochondrion has emerged as the key control point for steroidogenesis. The adrenal cortex is not alone in requiring efficient and controlled delivery of cholesterol into mitochondria. Other steroidogenic cells, including several cell types in the ovary, the Leydig cells of the testis, and a subset of hippocampal neurons (1), also employ P450scc to produce pregnenolone and a variety of downstream steroid hormones or neurosteroids. In vertebrates ranging from birds and fish (2) to mammals, these various cell types all express a short-lived mitochondrial import factor now called the steroidogenic acute regulatory protein (StAR), which mediates this process. Here, I examine the often confusing literature on StAR’s mechanism of action, particularly in light of recent work establishing the importance of other players, and I present a model for StAR’s interaction with cholesterol and with some of these other proteins. I also discuss the insights into mitochondrial function that have come from the analysis of patients with congenital adrenal hyperplasia (CAH), who lack this factor. Finally, I consider the multi-tiered regulation of StAR and related proteins in adrenocortical cells and other steroidogenic cell types.