Oxygen tolerance and coupling of mitochondrial electron transport.
Oxygen is critical to aerobic metabolism, but excessive oxygen (hyperoxia) causes cell injury and death. An oxygen-tolerant strain of HeLa cells, which proliferates even under 80% O2, termed "HeLa-80," was derived from wild-type HeLa cells ("HeLa-20") by selection for resistance to stepwise increases of oxygen partial pressure. Surprisingly, antioxidant defenses and susceptibility to oxidant-mediated killing do not differ between these two strains of HeLa cells. However, under both 20 and 80% O2, intracellular reactive oxygen species (ROS) production is significantly (approximately 2-fold) less in HeLa-80 cells. In both cell lines the source of ROS is evidently mitochondrial. Although HeLa-80 cells consume oxygen at the same rate as HeLa-20 cells, they consume less glucose and produce less lactic acid. Most importantly, the oxygen-tolerant HeLa-80 cells have significantly higher cytochrome c oxidase activity (approximately 2-fold), which may act to deplete upstream electron-rich intermediates responsible for ROS generation. Indeed, preferential inhibition of cytochrome c oxidase by treatment with n-methyl protoporphyrin (which selectively diminishes synthesis of heme a in cytochrome c oxidase) enhances ROS production and abrogates the oxygen tolerance of the HeLa-80 cells. Thus, it appears that the remarkable oxygen tolerance of these cells derives from tighter coupling of the electron transport chain.
Molecular Targets Group, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA.
Jian Li
JL
Campian
Mingwei
M
Qian
Xueshan
X
Gao
John W
JW
Eaton
D000154:Aconitate Hydratase / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D049109:Cell Proliferation; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D004583:Electrons; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D010313:Partial Pressure; D010545:Peroxides / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism; D017382:Reactive Oxygen Species; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D000975:Antioxidants; D007476:Ionophores; D007773:Lactates; D010545:Peroxides; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D005973:Glutamine; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004492:Edetic Acid; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D000154:Aconitate Hydratase; D005947:Glucose; D010100:Oxygen