Document Detail

Cytochrome c release is required for phosphatidylserine peroxidation during Fas-triggered apoptosis in lung epithelial A549 cells.
MedLine Citation:
PMID:  15726829     Owner:  NLM     Status:  MEDLINE    
Oxidation of phosphatidylserine (PtdSer) has been shown to play a pivotal role in signaling during cell apoptosis and subsequent recognition of apoptotic cells by phagocytes. However, the redox catalytic mechanisms involved in selective PtdSer oxidation during apoptosis remain poorly understood. Here we employed anti-Fas antibody CH-11-treated A549 cells as a physiologically relevant model to investigate the involvement of PtdSer oxidation and its potential mechanism during apoptosis. We demonstrated that ligation of CH-11 with its cognate receptor initiated execution of apoptotic program in interferon gamma-pretreated A549 cells as evidenced by activation of caspase and DNA fragmentation. A significant increase of cytochrome c (cyt c) content in the cytosol as early as 2 h after CH-11 exposure was detected indicating that Fas-induced apoptosis in A549 cells proceeds via extrinsic type II pathway and includes mitochondrial signaling. PtdSer was selectively oxidized 3 h after anti-Fas triggering while two more abundant phospholipids--phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn)--and the major intracellular antioxidant, glutathione, remained nonoxidized. A pan-caspase inhibitor, z-VAD, fully blocked cyt c release and oxidation of PtdSer in Fas-treated A549 cells. On the other hand, z-DQMD, a caspase-3 inhibitor, completely inhibited caspase-3 activity but did not fully block caspase-8 activation and release of cyt c. Importantly, z-DQMD failed to protect PtdSer from oxidation. In addition, in a model system, we demonstrated that peroxidase activity of cyt c was greatly enhanced in the presence of dioleoylphosphatidylserine containing liposomes by monitoring oxidation of 2',7'-dichlorodihydrofluorescein to 2',7'-dichlorofluorescein. We further showed that peroxidase activity of cyt c catalyzed oxidation of 1-palmitoyl-2-arachidonoyl-3-glycero-phosphoserine using a newly developed HPLC assay. MS analysis of 1-palmitoyl-2-arachidonoyl-3-glycero-phosphoserine revealed that in addition to its mono- and dihydroperoxides, several different PtdSer oxidation products can be formed. Overall, we concluded that cyt c acts as a catalyst of PtdSer oxidation during Fas-triggered A549 cell apoptosis.
Jianfei Jiang; Vidisha Kini; Natalia Belikova; Behice F Serinkan; Grigory G Borisenko; Yulia Y Tyurina; Vladimir A Tyurin; Valerian E Kagan
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Lipids     Volume:  39     ISSN:  0024-4201     ISO Abbreviation:  Lipids     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2005-02-24     Completed Date:  2005-05-25     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0060450     Medline TA:  Lipids     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1133-42     Citation Subset:  IM    
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
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MeSH Terms
Antibodies / immunology
Antigens, CD95 / metabolism*
Caspase 8
Caspases / metabolism
Cell Line, Tumor
Cytochromes c / metabolism*
Epithelial Cells / cytology*,  drug effects,  metabolism*
Interferon-gamma / pharmacology
Lipid Peroxidation*
Lung / cytology
Mass Spectrometry
Phosphatidylserines / metabolism*
Protease Inhibitors / pharmacology
Grant Support
Reg. No./Substance:
0/Antibodies; 0/Antigens, CD95; 0/Phosphatidylserines; 0/Protease Inhibitors; 82115-62-6/Interferon-gamma; 9007-43-6/Cytochromes c; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspases

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