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Submitted on March 5, 2003
Accepted on August 25, 2003
1 Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel, Department of Electronics, Jerusalem College of Technology, Jerusalem, Israel, Department of Physiology, University of Illinois at Chicago, Chicago, Illinois 60612-7342 USA, Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430 USA
* To whom correspondence should be addressed. E-mail: orly{at}vms.huji.ac.il.
Steroidogenic Acute Regulatory (StAR) protein is a nuclear encoded mitochondrial protein that enhances steroid synthesis by facilitating the transfer of cholesterol to the inner membranes of mitochondria in hormonally regulated steroidogenic cells. It is currently assumed that StAR activity commences before, or during StAR import into the mitochondrial matrix. The present study was designed to demonstrate that, once imported and becoming physiologically irrelevant, exhaustive accumulation of StAR must be limited by a rapid degradation of the protein to prevent potential damage to the organelles. The use of uncouplers and manipulation of the interior mitochondrial pH in hormone induced ovarian granulosa cells and StAR expressing COS cells, suggest that StAR degradation is bi-phasic and involves two classes of proteases. During Phase I, which normally lasts for the first 
2 h following import, StAR is rapidly degraded by a protease, or proteases, that can be arrested by a non-classical action of proteasome inhibitors such as MG132. StAR molecules that evade Phase I, are subjected to a second class of protease(s), which is slower and MG132-resistant. A third proteolytic entity was revealed in studies with C-28 StAR, a loss-of-function mutant of StAR. Upon initiation of its import, C-28 StAR dissipates the inner membrane potential and causes swelling of the mitochondria. Degradation of C-28 StAR, probably by an inter-membrane space protease, is extremely rapid MG132-insensitive. Collectively, this study defines StAR as the first naturally occurring mitochondrial protein that can serve as a substrate to probe multiple proteolytic activities in mammalian mitochondria.
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