"Wages of fear": transient threefold decrease in intracellular ATP level imposes apoptosis.
In HeLa cells, complete inhibition of oxidative phosphorylation by oligomycin, myxothiazol or FCCP combined with partial inhibition of glycolysis by DOG resulted in a steady threefold decrease in the intracellular ATP level. The ATP level recovers when the DOG-containing medium was replaced by that with high glucose. In 48 h after a transient (3 h) [ATP] lowering followed by recovery of the ATP level, the majority of the cells commits suicide by means of apoptosis. The cell death does not occur if DOG or an oxidative phosphorylation inhibitor was added separately, treatments resulting in 10-35% lowering of [ATP]. Apoptosis is accompanied by Bax translocation to mitochondria, cytochrome c release into cytosol, caspase activation, reactive oxygen species (ROS) generation, and reorganization and decomposition of chromatin. Apoptosis appears to be sensitive to oncoprotein Bcl-2 and a pancaspase inhibitor zVADfmk. In the latter case, necrosis is shown to develop instead of apoptosis. The cell suicide is resistant to cyclosporine A, a phospholipase inhibitor trifluoroperazine, the JNK and p38 kinase inhibitors, oligomycin, N-acetyl cysteine and mitoQ, differing in these respects from the tumor necrosis factor (TNF)- and H(2)O(2)-induced apoptoses. It is suggested that the ATP concentration in the cell is monitored by intracellular "ATP-meter(s)" generating a cell suicide signal when ATP decreases, even temporarily, below some critical level (around 1 mM).
Department of Bioenergetics, Belozersky Institute of Physico-Chemical Biology, Moscow State University, Khokhlova Street 4, Moscow 119992, Russian Federation.
Denis S
DS
Izyumov
Armine V
AV
Avetisyan
Olga Yu
OY
Pletjushkina
Dmitrii V
DV
Sakharov
Karel W
KW
Wirtz
Boris V
BV
Chernyak
Vladimir P
VP
Skulachev
D000255:Adenosine Triphosphate / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008689:Methacrylates; D008928:Mitochondria / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004791:Enzyme Inhibitors; D008689:Methacrylates; D009840:Oligomycins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013844:Thiazoles; D051028:bcl-2-Associated X Protein; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C030517:myxothiazol; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D003847:Deoxyglucose; D020169:Caspases