Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: Role of mitochondrial permeability transition

Whiteman, Matthew; Rose, Peter; Jia, Ling Siau; Nam, Sang Cheung; Gek, San Tan; Halliwell, Barry; Armstrong, Jeffrey S.

Abstract

Liver cirrhosis is often preceded by overt signs of hepatitis, including parenchymal cell inflammation and infiltration of polymorphonuclear (PMN) leukocytes. Activated PMNs release both reactive oxygen species and reactive halogen species, including hypochlorous acid (HOCl), which are known to be significantly cytotoxic due to their oxidizing potential. Because the role of mitochondria in the hepatotoxicity attributed to HOCl has not been elucidated, we investigated the effects of HOCl on mitochondrial function in the human hepatoma HepG2 cell line, human fetal liver cells, and isolated rat liver mitochondria. We show here that HOCl induced mitochondrial dysfunction, and apoptosis was dependent on the induction of the mitochondrial permeability transition (MPT), because HOCl induced mitochondrial swelling and collapse of the mitochondrial membrane potential with the concomitant release of cytochrome c. These biochemical events were inhibited by the classical MPT inhibitor cyclosporin A (CSA). Cell death induced by HOCl exhibited several classical hallmarks of apoptosis, including annexin V labeling, caspase activation, chromatin condensation, and cell body shrinkage. The induction of apoptosis by HOCl was further supported by the finding that CSA and caspase inhibitors prevented cell death. For the first time, these results show that HOCl activates the MPT, which leads to the induction of apoptosis and provides a novel insight into the mechanisms of HOCl-mediated cell death at sites of chronic inflammation. © 2005 Elsevier Inc. All rights reserved.

Citation

Whiteman, M., Rose, P., Jia, L. S., Nam, S. C., Gek, S. T., Halliwell, B., & Armstrong, J. S. (2005). Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: Role of mitochondrial permeability transition. Free Radical Biology and Medicine, 38(12), 1571-1584. https://doi.org/10.1016/j.freeradbiomed.2005.02.030

• Journal Article Type: Article
• Acceptance Date: Feb 18, 2005
• Online Publication Date: Mar 19, 2005
• Publication Date: Jun 15, 2005
• Deposit Date: Jan 29, 2025
• Journal: Free Radical Biology and Medicine
• Print ISSN: 0891-5849
• Electronic ISSN: 1873-4596
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 38
• Issue: 12
• Pages: 1571-1584
• DOI: https://doi.org/10.1016/j.freeradbiomed.2005.02.030
• Keywords: Hypochlorous acid, Inflammation, Cell toxicity, Liver, Apoptosis, Free radicals
• Public URL: https://nottingham-repository.worktribe.com/output/3219680
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0891584905000900?via%3Dihub