Figure 2.

Evolution of mitochondrial cholesterol import models. Cholesterol transport to the IMM and its conversion to pregnenolone by P450scc are essential steps for all steroid hormone production. The first generation of models indicated that StAR could independently accomplish cholesterol import to the IMM: 1) StAR was carried by chaperones and entered mitochondria creating “contact sites” between the outer and IMMs. Cholesterol is able to cross from the outer to the IMM at these contact sites. On entering the matrix, StAR is assembled, cleaved, and subsequently degraded. 2) StAR worked at the level of the mitochondrial intermembrane space shuttling cholesterol from the outer to the IMM. 3) StAR could bind and carry cholesterol in one direction across to the IMM, then enters the matrix to be cleaved and subsequently degraded. The second generation of models appeared after TSPO was introduced as a functional partner for StAR action: 4) StAR resided in the OMM and delivered cholesterol to TSPO that acted as a cholesterol channel to directly transport it to the IMM through contact sites between the 2 membranes. This could explain why N-terminal StAR truncation (N62-StAR) that disrupts its mitochondrial targeting and the Tom20-StAR fusion protein that resides in the OMM could still mediate cholesterol import. Given the new information on TSPO and its high-resolution structure, these elements need to be modified. In addition, recent information suggests that movement of StAR and cleavage/degradation in the mitochondrial matrix might be a terminal event that occurs after its function is completed. Therefore, existing questions are: 5) Is there a channel at the level of the OMM that is essential for cholesterol import? Is there a mechanism that shuttles cholesterol across the intermembrane space? Do we completely understand the mechanism of StAR action? These are topics that will require investigation.