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Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4.

Alisa A Garaeva1,2, Irina E Kovaleva3, Peter M Chumakov2

  • 1a Department of Bioengineering and Bioinformatics , Lomonosov Moscow State University , Moscow , Russia.

Cell Cycle (Georgetown, Tex.)
|January 16, 2016
PubMed
Summary

Mitochondrial dysfunction induces SESN2 gene transcription via ATF4, independent of p53. This stress response aids cell adaptation to low energy environments.

Keywords:
ATF4-binding siteISRIBSESN2 promoterSestrin 2integrated stress responsemitochondrial respiratory chain complex IIItranscription factor ATF4tumor suppressor p53

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The SESN2 gene is crucial for cellular stress response and homeostasis.
  • Mitochondrial dysfunction can impact cellular signaling pathways.
  • The role of p53 in stress-induced gene expression is well-established.

Purpose of the Study:

  • To investigate the mechanism by which mitochondrial respiratory chain inhibitors induce SESN2 gene transcription.
  • To determine the involvement of p53 and the integrated stress response (ISR) in this process.
  • To identify the transcription factors and regulatory elements controlling SESN2 expression under mitochondrial stress.

Main Methods:

  • Treatment of epithelial carcinoma cell lines with mitochondrial respiratory chain inhibitors (myxothiazol, piericidin A).
  • Analysis of p53 and ATF4 activation using Western blotting and qPCR.
  • Assessment of SESN2 transcript levels via qPCR.
  • Inhibition of ISR using ISRIB and manipulation of ATF4 expression via shRNA and overexpression constructs.
  • Luciferase reporter assays to confirm ATF4 binding site functionality.

Main Results:

  • Myxothiazol and piericidin A induced SESN2 transcription independently of p53 activation.
  • SESN2 induction occurred upstream of p53 activation and in p53-deficient cells.
  • Respiratory chain inhibitors triggered the integrated stress response (ISR) and induced ATF4.
  • ATF4 was confirmed as the key transcription factor for SESN2 upregulation via ISR.
  • A functional ATF4 binding site upstream of the SESN2 gene was identified.

Conclusions:

  • Mitochondrial dysfunction upregulates SESN2 transcription through the ATF4-mediated integrated stress response, independent of p53.
  • This pathway represents a homeostatic feedback mechanism to attenuate biosynthesis during energy deficits.
  • SESN2 induction enhances cellular adaptation and viability in hostile environments characterized by mitochondrial dysfunction.