Grant: Operating Grant

Eukaryotic steroid hormones are responsible for the maintenance of the organism's homeostasis, adaptability to the environment, and developmental and reproductive functions. Many tissues of the body have the ability to metabolize steroids. However, few tissues are able to synthesize steroid hormones from the substrate cholesterol. These tissues are the adrenals, gonads, placenta and brain. Steroidogenesis in adrenal and gonadal cells and its regulation by peptide trophic hormones has been well studied. The primary point of control of the acute stimulation of steroidogenesis by hormones and by the second messenger cAMP, involves the first step in this biosynthetic pathway where cholesterol is converted to pregnenolone by a cytochrome P450 enzyme, localized at the inner mitochondrial membrane. Pregnenolone then leaves the mitochondrion to undergo enzymatic transformation in the endoplasmic reticulum that will give rise to the final steroid products. The rate-determining step in this pathway is the transport of the precursor, cholesterol, from intracellular stores into mitochondria. To date, there are many questions on the mechanisms allowing minimal hormone and cAMP levels to induce maximal stimulation of cholesterol transport and steroid formation by the cells within minutes. This application deals with the mechanisms underlying the hormone-induced transport of substrate cholesterol from intracellular stores into the mitochondria. This intracellular trafficking of cholesterol is a fundamental aspect of cell biology and critical in reproductive and adrenal biology, since this is the rate-determining step in the formation of steroids. Understanding the mechanisms underlying this process would also pave the way for the development of novel pharmacological strategies for manipulation of the reproductive and adrenal function and might help unveiling the physiopathology of endocrine diseases associated with abnormal cholesterol metabolism and steroid synthesis.