Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax.

Free Radical Biology & Medicine
Neal B BlattG D Glick

Abstract

Bz-423 is a proapoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen-activated protein kinase cascade follows, leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent on both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevents Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that th...Continue Reading

Citations

Jul 23, 2011·Antioxidants & Redox Signaling·Jakub RohlenaJiri Neuzil
Aug 27, 2009·The Journal of Pharmacology and Experimental Therapeutics·Thomas B SundbergGary D Glick
Feb 22, 2012·Trends in Immunology·Valerie A Gerriets, Jeffrey C Rathmell
Jun 2, 2009·Biochemical Pharmacology·Neal B BlattGary D Glick
Sep 4, 2015·Brain Research·Kenji SudoKazuyuki Nakajima
Jul 2, 2009·Expert Opinion on Therapeutic Patents·Alexander M Abdelnoor
May 15, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Victor TkachevCraig A Byersdorfer
Jul 20, 2018·Frontiers in Physiology·Ilka StarkeMichael Börsch
Oct 19, 2021·ACS Pharmacology & Translational Science·Yu PanChun Loong Ho

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