Cholesterol traverses the cytosol and the mitochondrial intermembrane space complexed with carrier proteins. This process is essential for the synthesis of steroid hormones in humans. Nevertheless, molecular details of the transport process remain incomplete. A plausible model, supported by studies in vitro and in cells overexpressing cloned human proteins, is that cytosolic StAR-related cholesterol-binding proteins STARD3, 4, and 6 bind cholesterol liberated from lysosomes or cytosolic lipid droplets and carry it to the outer mitochondrial membrane (Rodriguez-Aguado et al. 2005; Soccio et al. 2002). Here, it is transferred to the steroidogenic acute regulatory protein (STAR) and carried across the mitochondrial intermembrane space (Miller 2007, Letourneau et al. 2015).
Mutations in the gene encoding STAR block synthesis of all steroid hormones in humans, indicating the critical importance of this transport step in the biosynthetic process (Bose et al. 1996). The transport step is also a key site for normal regulation of steroid hormone synthesis, as STAR protein is unstable and its synthesis is up-regulated in response to signals such as the binding of ACTH to its receptors on adrenal cells (Stocco 2001).