Potentiation of Fas-mediated apoptosis by attenuated production of mitochondria-derived reactive oxygen species.
The role of reactive oxygen species (ROS) production in death receptor-mediated apoptosis is ill-defined. Here, we show that ROS levels play a role in moderating Fas-dependent apoptosis. Treatment of Jurkat T cells with oligomycin (ATP-synthase inhibitor) or (mitochondrial uncoupler) and Fas-activating antibody (CH11) facilitated rapid cell death that was not associated with decreased ATP production or increased DEVDase activity and cytochrome c release. However, a decrease in cellular ROS production was associated with CH11 treatment, and combinations of CH11 with oligomycin or FCCP further inhibited cellular ROS production. Thus, decreased ROS production is correlated with enhanced cell death. A transition from state 3 to state 4 mitochondrial respiration accounted for the attenuated ROS production and membrane potential. Similar observations were demonstrated in isolated rat liver mitochondria. These data show that ROS production is important in receptor-mediated apoptosis, playing a pivotal role in cell survival.
Aronis
A
A
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
Melendez
J Andr's
JA
Golan
O
O
Shilo
S
S
Dicter
N
N
Tirosh
O
O
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D017209:Apoptosis; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D016923:Cell Death; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D010957:Plasmids / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
D002843:Chromatin; D004791:Enzyme Inhibitors; D009840:Oligomycins; D016877:Oxidants; D017382:Reactive Oxygen Species; D019014:fas Receptor; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D010100:Oxygen