title: Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin-2 and Peroxiredoxin-3 during Hyperoxic Injury.
abstract: Mitochondria play a fundamental role in the regulation of cell death during accumulation of oxidants. High concentrations of atmospheric oxygen (hyperoxia), used clinically to treat tissue hypoxia in premature newborns, is known to elicit oxidative stress and mitochondrial injury to pulmonary epithelial cells. A consequence of oxidative stress in mitochondria is the accumulation of peroxides which are detoxified by the dedicated mitochondrial thioredoxin system. This system is comprised of the oxidoreductase activities of peroxiredoxin-3 (Prx3), thioredoxin-2 (Trx2), and thioredoxin reductase-2 (TrxR2). The goal of this study was to understand the role of the mitochondrial thioredoxin system and mitochondrial injuries during hyperoxic exposure. Flow analysis of the redox-sensitive, mitochondrial-specific fluorophore, MitoSOX, indicated increased levels of mitochondrial oxidant formation in human adenocarcinoma cells cultured in 95% oxygen. Increased expression of Trx2 and TrxR2 in response to hyperoxia were not attributable to changes in mitochondrial mass, suggesting that hyperoxic upregulation of mitochondrial thioredoxins prevents accumulation of oxidized Prx3. Mitochondrial oxidoreductase activities were modulated through pharmacological inhibition of TrxR2 with auranofin and genetically through shRNA knockdown of Trx2 and Prx3. Diminished Trx2 and Prx3 expression was associated with accumulation of mitochondrial superoxide; however, only shRNA knockdown of Trx2 increased susceptibility to hyperoxic cell death and increased phosphorylation of apoptosis signal-regulating kinase-1 (ASK1). In conclusion, the mitochondrial thioredoxin system regulates hyperoxic-mediated death of pulmonary epithelial cells through detoxification of oxidants and regulation of redox-dependent apoptotic signaling.
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Forred
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Darwin R
authors.initials: DR
authors.lastname: Daugaard
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Brianna K
authors.initials: BK
authors.lastname: Titus
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Wood
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Floen
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Booze
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.|Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, United States of America.
authors.forename: Peter F
authors.identifier: http://orcid.org/0000-0001-5344-9192
authors.initials: PF
authors.lastname: Vitiello
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D018496:Hyperoxia; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D061105:Peroxiredoxin III / Q000378:metabolism*; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D016877:Oxidants; C467002:TXN2 protein, human; D013879:Thioredoxins; D061105:Peroxiredoxin III; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D010100:Oxygen