The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways

Whiteman, Matthew and Chu, Siew Hwa and Siau, Jia Ling and Rose, Peter and Sabapathy, Kanaga and Schantz, Jan-Thorsten and Cheung, Nam Sang and Spencer, Jeremy P.E. and Armstrong, Jeffrey S. (2007) The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways. Cellular Signalling, 19 (4). pp. 705-714. ISSN 0898-6568

Full content URL: http://dx.doi.org/10.1016/j.cellsig.2006.08.019

Full text not available from this repository.

Item Type:Article
Item Status:Live Archive

Abstract

At sites of chronic inflammation, such as in the inflamed rheumatoid joint, activated neutrophils release hydrogen peroxide (H2O2) and the enzyme myeloperoxidase to catalyse the formation of hypochlorous acid (HOCl). 3-chlorotyrosine, a marker of HOCl in vivo, has been observed in synovial fluid proteins from rheumatoid arthritis patients. However the mechanisms of HOCl-induced cytotxicity are unknown. We determined the molecular mechanisms by which HOCl induced cell death in human mesenchymal progenitor cells (MPCs) differentiated into a chondrocytic phenotype as a model of human cartilage cells and show that HOCl induced rapid Bax conformational change, mitochondrial permeability and release of intra-mitochondrial pro-apoptotic proteins which resulted in nuclear translocation of AIF and EndoG. siRNA-mediated knockdown of Bax substantially prevented mitochondrial permeability, release of intra-mitochondrial pro-apoptotic proteins. Cell death was inhibited by siRNA-mediated knockdown of Bax, AIF or EndoG. Although we observed several biochemical markers of apoptosis, caspase activation was not detected either by western blotting, fluorescence activity assays or by using caspase inhibitors to inhibit cell death. This was further supported by findings that (1) in vitro exposure of recombinant human caspases to HOCl caused significant inhibition of caspase activity and (2) the addition of HOCl to staurosporine-treated MPCs inhibited the activity of cellular caspases. Our results show for the first time that HOCl induced Bax-dependent mitochondrial permeability which led to cell death without caspase activity by processes involving AIF/EndoG-dependent pathways. Our study provides a novel insight into the potential mechanisms of cell death in the inflamed human joint.

Keywords:Hypochlorous acid, Oxidative stress, Bax, Mitochondria, Arthritis, Cell death
Subjects:B Subjects allied to Medicine > B131 Cellular Pathology
Divisions:College of Science > School of Life Sciences
ID Code:11956
Deposited On:19 Sep 2013 15:37

Repository Staff Only: item control page