“Wages of Fear”: transient threefold decrease in intracellular ATP level imposes apoptosis

Abstract

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).

Targeted Expression of Uncoupling Protein 2 to Mouse Liver Increases the Susceptibility to Lipopolysaccharide/Galactosamine-Induced Acute Liver Injury†

“…The apoptosis related to ATP depletion could be inhibited by JNK inhibition. 22,41 A better understanding of the mechanism of UCP2 in cell death holds promise for fighting liver diseases and metabolic disorders.…”

“…To understand the mechanism of how UCP2 promotes liver injury, we asked whether the reduced levels of ATP contributed to the increased sensitivity to liver injury because a decrease of intracellular ATP levels was found to activate cellular signaling pathways and to promote cell death. 22 We measured the ATP levels in the liver after LPS/GalN treatment and found a greater reduction of ATP levels in Tg mice livers (Fig. 6A).…”

“…9-11 On the contrary, it may lead to ATP depletion or even energy crisis that may promote cell death. 22 UCP2 protein is not expressed in hepatocytes in adult healthy liver but is restricted in Kupffer cell, although UCP2 messenger RNA (mRNA) is detected in hepatocytes. 23 An interesting note is that UCP2 expression becomes significantly abundant in hepatocytes of fatty liver, steatotic liver, and chronic liver disease conditions.…”

Cofactor Strap regulates oxidative phosphorylation and mitochondrial p53 activity through ATP synthase

“…31 During apoptosis, a sufficient supply of ATP is necessary to favour apoptosome formation and trigger caspase activation, 32 and the severity of reduction in cellular ATP often determines the mode of programmed cell death. 32 A decrease in intracellular ATP can initiate cytochrome c release from the inner mitochondrial membrane and trigger apoptosis; 33 in this respect, overexpression of L-Strap resulted in a decrease in the ATP/ADP ratio and was able to sensitise the cells to p53-dependent apoptosis.…”

Sodium citrate inhibits the proliferation of human gastric adenocarcinoma epithelia cells

“…During glycolysis, citrate acts as an inhibitor of phosphofructokinase and may obstruct the production of ATP or macromolecular precursors, causing the typical cytotoxicity in cancer cells, as has been confirmed in malignant pleural mesothelioma cells (10). Cells deficient in ATP frequently undergo apoptosis (11,12); the induction of cell apoptosis via citrate has been demonstrated in unicellular organisms as well as cancer cells (13,14).…”