Mechanism of StAR's regulation of mitochondrial cholesterol import

Abstract

The steroidogenic acute regulatory protein (StAR) mediates the acute steroidogenic response by moving cholesterol from the outer to inner mitochondrial membrane, but the mechanism of StAR's action has remained mysterious. We showed that StAR acts on the outer membrane, requires cholesterol binding, and requires the structural change previously described as a pH-dependent molten globule. The current model is that StAR's interaction with protonated phospholipid head groups on the outer mitochondrial membrane induces a molten globule transition needed for StAR to take up cholesterol. Recent data suggest a functional interaction between StAR and the peripheral benzodiazepine receptor (PBR). Whereas many models have suggested that StAR delivers cholesterol to PBR, we suggest that StAR removes cholesterol from the cholesterol-binding domain of PBR and delivers it to the inner mitochondrial membrane.