ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis

Ritesh K. Srivastava, Changzhao Li, Aftab Ahmad, Onika Abrams, Marina S. Gorbatyuk, Kevin S. Harrod, Ronald Wek, Farrukh Afaq, Mohammad Athar

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4+/+ and ATF4−/− MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4+/+ MEF cells which is largely ablated upon loss of ATF4. Following ATO treatment, ATF4 activates NADPH oxidase by promoting assembly of the enzyme components Rac-1/P47phox/P67phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca++/calpain/caspase-12-mediated apoptosis following ATO treatment. The IP3R inhibitor attenuates Ca++/calpain-dependent apoptosis, as well as reduces m-ROS and MMP disruption, suggesting that ER-mitochondria crosstalk involves IP3R-regulated Ca++ signaling. Blockade of m-Ca++ entry by inhibiting m-VDAC reduces ATO-mediated UPR in ATF4+/+ cells. Additionally, ATO treatment leads to p53-regulated mitochondrial apoptosis, where p53 phosphorylation plays a key role. Together, these findings indicate that ATO-mediated apoptosis is regulated by both ER and mitochondria events that are facilitated by ATF4 and the UPR. Thus, we describe novel mechanisms by which ATO orchestrates cytotoxic responses involving interplay of ER and mitochondria.

Original languageEnglish (US)
Pages (from-to)39-50
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume609
DOIs
StatePublished - Nov 1 2016

Fingerprint

NADPH Oxidase
Crosstalk
Endoplasmic Reticulum
Unfolded Protein Response
Apoptosis
Mitochondria
Arsenic
Calpain
Proteins
Caspase 12
Phosphorylation
arsenic trioxide
Matrix Metalloproteinases
Superoxides
Toxicity
Derivatives
Enzymes

Keywords

  • Apoptosis
  • Arsenic
  • ATF4
  • Ca release
  • ER-mitochondria crosstalk

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Srivastava, R. K., Li, C., Ahmad, A., Abrams, O., Gorbatyuk, M. S., Harrod, K. S., ... Athar, M. (2016). ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis. Archives of Biochemistry and Biophysics, 609, 39-50. https://doi.org/10.1016/j.abb.2016.09.003

ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis. / Srivastava, Ritesh K.; Li, Changzhao; Ahmad, Aftab; Abrams, Onika; Gorbatyuk, Marina S.; Harrod, Kevin S.; Wek, Ronald; Afaq, Farrukh; Athar, Mohammad.

In: Archives of Biochemistry and Biophysics, Vol. 609, 01.11.2016, p. 39-50.

Research output: Contribution to journalArticle

Srivastava, RK, Li, C, Ahmad, A, Abrams, O, Gorbatyuk, MS, Harrod, KS, Wek, R, Afaq, F & Athar, M 2016, 'ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis', Archives of Biochemistry and Biophysics, vol. 609, pp. 39-50. https://doi.org/10.1016/j.abb.2016.09.003
Srivastava, Ritesh K. ; Li, Changzhao ; Ahmad, Aftab ; Abrams, Onika ; Gorbatyuk, Marina S. ; Harrod, Kevin S. ; Wek, Ronald ; Afaq, Farrukh ; Athar, Mohammad. / ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis. In: Archives of Biochemistry and Biophysics. 2016 ; Vol. 609. pp. 39-50.
@article{5c261635baf34c15b9b2df6da8f9b6b3,
title = "ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis",
abstract = "Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4+/+ and ATF4−/− MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4+/+ MEF cells which is largely ablated upon loss of ATF4. Following ATO treatment, ATF4 activates NADPH oxidase by promoting assembly of the enzyme components Rac-1/P47phox/P67phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca++/calpain/caspase-12-mediated apoptosis following ATO treatment. The IP3R inhibitor attenuates Ca++/calpain-dependent apoptosis, as well as reduces m-ROS and MMP disruption, suggesting that ER-mitochondria crosstalk involves IP3R-regulated Ca++ signaling. Blockade of m-Ca++ entry by inhibiting m-VDAC reduces ATO-mediated UPR in ATF4+/+ cells. Additionally, ATO treatment leads to p53-regulated mitochondrial apoptosis, where p53 phosphorylation plays a key role. Together, these findings indicate that ATO-mediated apoptosis is regulated by both ER and mitochondria events that are facilitated by ATF4 and the UPR. Thus, we describe novel mechanisms by which ATO orchestrates cytotoxic responses involving interplay of ER and mitochondria.",
keywords = "Apoptosis, Arsenic, ATF4, Ca release, ER-mitochondria crosstalk",
author = "Srivastava, {Ritesh K.} and Changzhao Li and Aftab Ahmad and Onika Abrams and Gorbatyuk, {Marina S.} and Harrod, {Kevin S.} and Ronald Wek and Farrukh Afaq and Mohammad Athar",
year = "2016",
month = "11",
day = "1",
doi = "10.1016/j.abb.2016.09.003",
language = "English (US)",
volume = "609",
pages = "39--50",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis

AU - Srivastava, Ritesh K.

AU - Li, Changzhao

AU - Ahmad, Aftab

AU - Abrams, Onika

AU - Gorbatyuk, Marina S.

AU - Harrod, Kevin S.

AU - Wek, Ronald

AU - Afaq, Farrukh

AU - Athar, Mohammad

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4+/+ and ATF4−/− MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4+/+ MEF cells which is largely ablated upon loss of ATF4. Following ATO treatment, ATF4 activates NADPH oxidase by promoting assembly of the enzyme components Rac-1/P47phox/P67phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca++/calpain/caspase-12-mediated apoptosis following ATO treatment. The IP3R inhibitor attenuates Ca++/calpain-dependent apoptosis, as well as reduces m-ROS and MMP disruption, suggesting that ER-mitochondria crosstalk involves IP3R-regulated Ca++ signaling. Blockade of m-Ca++ entry by inhibiting m-VDAC reduces ATO-mediated UPR in ATF4+/+ cells. Additionally, ATO treatment leads to p53-regulated mitochondrial apoptosis, where p53 phosphorylation plays a key role. Together, these findings indicate that ATO-mediated apoptosis is regulated by both ER and mitochondria events that are facilitated by ATF4 and the UPR. Thus, we describe novel mechanisms by which ATO orchestrates cytotoxic responses involving interplay of ER and mitochondria.

AB - Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4+/+ and ATF4−/− MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4+/+ MEF cells which is largely ablated upon loss of ATF4. Following ATO treatment, ATF4 activates NADPH oxidase by promoting assembly of the enzyme components Rac-1/P47phox/P67phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca++/calpain/caspase-12-mediated apoptosis following ATO treatment. The IP3R inhibitor attenuates Ca++/calpain-dependent apoptosis, as well as reduces m-ROS and MMP disruption, suggesting that ER-mitochondria crosstalk involves IP3R-regulated Ca++ signaling. Blockade of m-Ca++ entry by inhibiting m-VDAC reduces ATO-mediated UPR in ATF4+/+ cells. Additionally, ATO treatment leads to p53-regulated mitochondrial apoptosis, where p53 phosphorylation plays a key role. Together, these findings indicate that ATO-mediated apoptosis is regulated by both ER and mitochondria events that are facilitated by ATF4 and the UPR. Thus, we describe novel mechanisms by which ATO orchestrates cytotoxic responses involving interplay of ER and mitochondria.

KW - Apoptosis

KW - Arsenic

KW - ATF4

KW - Ca release

KW - ER-mitochondria crosstalk

UR - http://www.scopus.com/inward/record.url?scp=84988637907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988637907&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2016.09.003

DO - 10.1016/j.abb.2016.09.003

M3 - Article

C2 - 27638049

AN - SCOPUS:84988637907

VL - 609

SP - 39

EP - 50

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

ER -