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/P47^phox/P67^phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca

SUBMITTER: Srivastava RK 

PROVIDER: S-EPMC5077172 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature