title: StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation.
abstract: Steroidogenic acute regulatory protein (StAR) is essential for steroid hormone synthesis in the adrenal cortex and the gonads. StAR activity facilitates the supply of cholesterol substrate into the inner mitochondrial membranes where conversion of the sterol to a steroid is catalyzed. Mitochondrial import terminates the cholesterol mobilization activity of StAR and leads to mounting accumulation of StAR in the mitochondrial matrix. Our studies suggest that to prevent mitochondrial impairment, StAR proteolysis is executed by at least 2 mitochondrial proteases, ie, the matrix LON protease and the inner membrane complexes of the metalloproteases AFG3L2 and AFG3L2:SPG7/paraplegin. Gonadotropin administration to prepubertal rats stimulated ovarian follicular development associated with increased expression of the mitochondrial protein quality control system. In addition, enrichment of LON and AFG3L2 is evident in StAR-expressing ovarian cells examined by confocal microscopy. Furthermore, reporter studies of the protease promoters examined in the heterologous cell model suggest that StAR expression stimulates up to a 3.5-fold increase in the protease gene transcription. Such effects are StAR-specific, are independent of StAR activity, and failed to occur upon expression of StAR mutants that do not enter the matrix. Taken together, the results of this study suggest the presence of a novel regulatory loop, whereby acute accumulation of an apparent nuisance protein in the matrix provokes a mitochondria to nucleus signaling that, in turn, activates selected transcription of genes encoding the enrichment of mitochondrial proteases relevant for enhanced clearance of StAR.
authors.affiliation: Department of Biological Chemistry (A.B., S.P., J.O.) and Bio-Imaging Unit (N.M.-B.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; and Institute for Genetics (I.L., T.L.), Center for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Assaf
authors.initials: A
authors.lastname: Bahat
authors.forename: Shira
authors.initials: S
authors.lastname: Perlberg
authors.forename: Naomi
authors.initials: N
authors.lastname: Melamed-Book
authors.forename: Ines
authors.initials: I
authors.lastname: Lauria
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.forename: Joseph
authors.initials: J
authors.lastname: Orly
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics* / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004790:Enzyme Induction; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D010053:Ovary / Q000201:enzymology; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D049070:Protease La / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C508138:A-CREB protein; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D000098682:Steroidogenic Acute Regulatory Protein; D049069:ATP-Dependent Proteases; D049070:Protease La; C120699:AFG3L2 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities