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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ritesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Stillman College, 3601 Stillman Blvd, Tuscaloosa, AL, USA.
authors.forename: Onika
authors.initials: O
authors.lastname: Abrams
authors.affiliation: Department of Visual Science, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gorbatyuk
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: mathar@uab.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010087:Oxides / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
chemical_list: D001152:Arsenicals; C081452:Atf4 protein, mouse; D010087:Oxides; D017382:Reactive Oxygen Species; D013481:Superoxides; D051701:Activating Transcription Factor 4; D019255:NADPH Oxidases; D000077237:Arsenic Trioxide; D002118:Calcium
keywords: ATF4; Apoptosis; Arsenic; Ca(++) release; ER-mitochondria crosstalk