Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4

Abstract

We found that inhibitors of mitochondrial respiratory chain complexes III (myxothiazol) and I (piericidin A) in some epithelial carcinoma cell lines induce transcription of the p53-responsive SESN2 gene that plays an important role in stress response and homeostatic regulation. However, the effect did not depend on p53 because i) there was no induction of p53 after the treatment with piericidin A; ii) after the treatment with myxothiazol the peak of SESN2 gene upregulation occurred as early as 5h, before the onset of p53 activation (13h); iii) a supplementation with uridine that abolishes the p53 activation in response to myxothiazol did not abrogate the induction of SESN2 transcripts; iv) in the p53 negative HCT116 p53 -/- cells SESN2 transcription could be also induced by myxothiazol. In response to the respiratory chain inhibitors we observed an induction of ATF4, the key transcription factor of the integrated stress response (ISR). We found that the induction of SESN2 transcripts could be prevented by the ISR inhibitory small molecule ISRIB. Also, by inhibiting or overexpressing ATF4 with specific shRNA or ATF4-expressing constructs, respectively, we have confirmed the role of ATF4 in the SESN2 gene upregulation induced by mitochondrial dysfunction. At a distance of 228 bp upstream from the SESN2 transcription start site we found a candidate sequence for the ATF4 binding site and confirmed its requirement for the induction of SESN2 in luciferase reporter experiments. We suggest that the upregulation of SESN2 by mitochondrial dysfunction provides a homeostatic feedback that attenuates biosynthetic processes during temporal losses of energy supply from mitochondria thereby assisting better adaptation and viability of cells in hostile environments.

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

“…The genes encoding sestrins ( SESNs ) are induced by various types of stress including oxidative stress [11–13], mitochondrial dysfunction [14, 15], endoplasmic reticulum stress [16] and DNA damage [5, 11]. While invertebrate model species such as C .…”

Melatonin inhibits vascular smooth muscle cell proliferation and apoptosis through upregulation of Sestrin2

“…Sestrin2 is an important regulator of mitohormesis in diverse tissues, including skeletal/cardiac muscle and brown adipose tissue (9). Previous study demonstrated that inhibitors of mitochondrial respiratory chain complex I and III induce transcription of Sestrin2 (22). Here, we showed that melatonin-induced Sestrin2 upregulation is mediated by C/EBPβ, which is activated as an aspect of mitochondrial retrograde signaling in response to mitochondrial stress (23).…”

Mitochondrial localization of SESN2

“…Accordingly, the role of SESN2 in the support of mitophagy was recently reported [45,50,51]. These data are also supported by the activation of SESN2 in response to inhibitors of mitochondrial respiratory chain such as rotenone and piericidin A [16,52] that might indicate that SESN2 might be required to provide support of mitochondrial function in the conditions of mitochondrial stress. Another potential mitochondrial function of sestrins might be the regulation of cell death.…”