title: Mitochondrial metabolism underlies hyperoxic cell damage.
abstract: Exposure of mammals to hyperoxia causes pulmonary and ocular pathology. Hyperoxic damage and cell death may derive from enhanced intracellular formation of reactive oxygen species (ROS), probably of mitochondrial origin. There is, however, controversy on this point. When wild-type and respiration-deficient (rho(o)) HeLa cells were cultured in 80% O2, wild-type cells stopped growing after 5 days and died thereafter whereas rho(o) cells survived and grew to confluence. This tolerance of rho(o) cells for hyperoxia was not associated with greater resistance to oxidants such as hydrogen peroxide and t-butyl hydroperoxide. Under both 20% and 80% O2, rho(o) cells exhibited substantially decreased ROS production, and, under 80% O2, rho(o) cells showed no suppression of aconitase activity or mitochondrial protein carbonyl formation. Replacement of normal mitochondria in rho(o) cells restored ROS production and susceptibility to hyperoxia. Two other approaches that diminished mitochondrial ROS generation also increased tolerance for hyperoxia. HeLa cells constantly exposed to the protonophoric uncoupler carbonyl cyanide m-chlorophenylhydrazone, which enhances respiration but decreases ROS production, showed preferential survival under 80% O2, as did HeLa cells treated with chloramphenicol, which suppresses both respiration and mitochondrial ROS production. We conclude that interactions between respiring mitochondria and O2 are primarily responsible for hyperoxic cell damage.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Xueshan
authors.initials: X
authors.lastname: Gao
authors.forename: Mingwei
authors.initials: M
authors.lastname: Qian
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
mesh_terms: D001483:Base Sequence; D002455:Cell Division; D002470:Cell Survival; D017931:DNA Primers; D006367:HeLa Cells; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species
chemical_list: D017931:DNA Primers; D017382:Reactive Oxygen Species