Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin-2 and Peroxiredoxin-3 during Hyperoxic Injury

Authors

Benjamin J. Forred, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Darwin R. Daugaard, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Brianna K. Titus, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Ryan R. Wood, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Miranda J. Floen, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Michelle L. Booze, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota
Peter F. Vitiello, Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota

Document Type

Article

Date of this Version

2017

Citation

Forred BJ, Daugaard DR, Titus BK, Wood RR, Floen MJ, Booze ML, et al. (2017) Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin- 2 and Peroxiredoxin-3 during Hyperoxic Injury. PLoS ONE 12(1): e0168777.

Comments

Copyright © 2017 Forred et al. This is an open access article distributed under the terms of the Creative Commons Attribution License

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.