Mitochondrial state 3 to 4 respiration transition during Fas-mediated apoptosis controls cellular redox balance and rate of cell death.
The role of reactive oxygen species (ROS) production in death receptor-mediated apoptosis is ill defined. We show that ROS levels play a novel role in moderating the rate of cell death in Fas-dependent apoptosis. Treatment of Jurkat T cells with oligomycin (ATP-synthase inhibitor) or FCCP (mitochondrial uncoupler) and Fas activating antibody (CH11), facilitated rapid cell death. ATP levels, DEVDase activity and cytochrome c release were not account for the synergistic killing effect. However, a decrease in cellular ROS production was associated with CH11 treatment and combinations of CH11 with oligomycin or FCCP further inhibited cellular ROS levels. Thus, decreased ROS production is correlated with accelerated cell death. A transition from state 3 to state 4 mitochondrial respiration following apoptotic stimuli accounted for an attenuated membrane potential and as a results mitochondria-derived ROS production capacity diminished. Similar observations were demonstrated in isolated rat liver mitochondria. Transfection with mitochondrial targeted catalase inhibited mitochondrial ROS production and potentiated cell death. These data show that ROS production is important in receptor-mediated apoptosis and may play a pivotal role in cell survival.
Tirosh
Oren
O
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel. otirosh@agri.huji.ac.il
Aronis
Anna
A
Melendez
J Andr's
JA
D017209:Apoptosis; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D009840:Oligomycins / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019014:fas Receptor / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D009840:Oligomycins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D025261:Mitochondrial Proton-Translocating ATPases