StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation

Mol Endocrinol. 2014 Feb;28(2):208-24. doi: 10.1210/me.2013-1275. Epub 2013 Jan 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases / genetics*
  • ATP-Dependent Proteases / metabolism
  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Enzyme Induction
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism
  • Mitochondria / enzymology*
  • Ovary / enzymology
  • Phosphoproteins / physiology*
  • Promoter Regions, Genetic
  • Protease La / genetics
  • Protease La / metabolism
  • Proteolysis
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transcription, Genetic

Substances

  • A-CREB protein
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • steroidogenic acute regulatory protein
  • ATP-Dependent Proteases
  • Protease La
  • AFG3L2 protein, human
  • Metalloendopeptidases
  • SPG7 protein, human
  • ATPases Associated with Diverse Cellular Activities

Grant support

This work was supported by the Israel Science Foundation (1558/07 and 677/12 to J.O.), the Ori Foundation in memory of Ori Levi (A.B.), and the Deutsche Forschungsgemeinschaft (grants SFB635 and C4) and the European Research Council (AdG No. 233078 to T.L.).