Transcriptional activation of LON Gene by a new form of mitochondrial stress: A role for the nuclear respiratory factor 2 in StAR overload response (SOR).
High output of steroid hormone synthesis in steroidogenic cells of the adrenal cortex and the gonads requires the expression of the steroidogenic acute regulatory protein (StAR) that facilitates cholesterol mobilization to the mitochondrial inner membrane where the CYP11A1/P450scc enzyme complex converts the sterol to the first steroid. Earlier studies have shown that StAR is active while pausing on the cytosolic face of the outer mitochondrial membrane while subsequent import of the protein into the matrix terminates the cholesterol mobilization activity. Consequently, during repeated activity cycles, high level of post-active StAR accumulates in the mitochondrial matrix. To prevent functional damage due to such protein overload effect, StAR is degraded by a sequence of three to four ATP-dependent proteases of the mitochondria protein quality control system, including LON and the m-AAA membranous proteases AFG3L2 and SPG7/paraplegin. Furthermore, StAR expression in both peri-ovulatory ovarian cells, or under ectopic expression in cell line models, results in up to 3-fold enrichment of the mitochondrial proteases and their transcripts. We named this novel form of mitochondrial stress as StAR overload response (SOR). To better understand the SOR mechanism at the transcriptional level we analyzed first the unexplored properties of the proximal promoter of the LON gene. Our findings suggest that the human nuclear respiratory factor 2 (NRF-2), also known as GA binding protein (GABP), is responsible for 88% of the proximal promoter activity, including the observed increase of transcription in the presence of StAR. Further studies are expected to reveal if common transcriptional determinants coordinate the SOR induced transcription of all the genes encoding the SOR proteases.
Department of Biological Chemistry at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Assaf
A
Bahat
Department of Biological Chemistry at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Shira
S
Perlberg
Bio-Imaging Unit at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Naomi
N
Melamed-Book
Department of Cell & Developmental Biology at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Sara
S
Isaac
Department of Cell & Developmental Biology at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Amir
A
Eden
CECAD Research Center, Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
Ines
I
Lauria
CECAD Research Center, Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
Thomas
T
Langer
Department of Biological Chemistry at the Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address: orly@vms.huji.ac.il.
Joseph
J
Orly
D000818:Animals; D001483:Base Sequence; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D049070:Protease La / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D000098682:Steroidogenic Acute Regulatory Protein
D051268:GA-Binding Protein Transcription Factor; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D049070:Protease La
LON transcription; StAR degradation; mitochondrial proteases