Endocrine Abstracts

Steroidogenic acute regulatory protein (StAR) is a nuclear encoded vital mitochondrial protein that is essential for synthesis of steroid hormones in the adrenal and gonads. In these tissues, StAR mediates translocation of cholesterol into the inner mitochondrial membranes, where it is converted to the first steroid, pregnenolone. The roughly understood mechanism of StAR action is probably executed prior to StAR import, when the protein is paused at the surface of the outer mitochondrial membrane. Import, therefore, is presently perceived as a turning-off mechanism of StAR activity and leads to a rapid and excessive accumulation of non-functional StAR in the mitochondrial matrix. We postulated that the latter imposes a potential ‘protein stress’ scenario requiring a rapid degradation of the protein to avoid organelle damage. This study shows that, indeed, StAR is a rare example of a mitochondrial protein with a short half-life that is subjected to proteolysis by a cascade of ATP-dependent mitochondrial proteases. First, Lon protease degrades StAR upon its entry into the matrix. Then, StAR molecules that survived Lon, readily adhere onto the surface of the inner membranes where an inner-membrane protease complex is involved in the second phase degradation of the protein. By use of over-expression, siRNA, pulse-chase and promoter analysis approaches, our results suggest that it is the AFG3L2 protease/chaperone homo-oligomeric complex that is responsible for StAR degradation in the second phase of it elimination; AFG3L2 together with paraplegin (SPG7) function as proteases and chaperons involved in protein quality control and mitochondrial morphology; also, loss-of-function mutations in the latter cause terminal neurodegenerative disorders such as hereditary spastic paraplegia. Our results suggest that turnover of non-functional StAR in the mitochondria is reassured by a succession of protease actions that are critical to maintain the critical function of steroidogenic mitochondria posed under ‘protein stress’ circumstances.