Cellular physiology and molecular events in hypoxia-induced apoptosis.
Malignant tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. The experimental evidence showing that hypoxia may have a profound impact on malignant progression and on responsiveness to therapy is growing. In fact hypoxia, like other genotoxic and non-genotoxic stresses, has been shown to increase the p53 protein level, and subsequently activate target genes like p21/waf-1 which interact with cell cycle machinery or participate in apoptosis. Apoptosis is a genetically encoded program of cell death that can be activated under physiological conditions like hypoxia, and may be an important safeguard against tumour development. One of the first common manifestations of the apoptotic process, irrespective of the cell type, is the disruption of mitochondrial membrane function, including a dissipation of the delta psi m and/or a modification on the mitochondrial release of protease activators. These modifications are linked to specific patterns of bioenergetic parameters i.e. respiratory flux, mitochondrial redox potential and phosphate potential. We have studied gluconeogenesis and glycolysis pathways in intact hepatocytes isolated from fasted rats submitted to 24 h of hypoxic in vivo exposure. We have shown that hypoxia resulted in an inhibition of the gluconeogenesis pathway due to a decrease in phosphoenolpyruvate carboxykinase (PEPCK) activity and mRNA synthesis in rat hepatocytes. In conclusion, the disruption of mitochondrial membrane function in response to different oxygen content such as periarterial or perivenous PO2 led to the inhibition of gluconeogenesis and apoptosis in hypoxic cells.
Riva
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Fundamental and Applied Bioenergetics Laboratory, Joseph Fourier University, Grenoble, France. catherine.riva-lavieille@ujf-grenoble.fr
Chauvin
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Pison
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Leverve
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D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D015687:Cell Hypoxia; D005943:Gluconeogenesis; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D051381:Rats
D010729:Phosphoenolpyruvate Carboxykinase (GTP)