Mitochondrial respiratory chain involvement in peroxiredoxin 3 oxidation by phenethyl isothiocyanate and auranofin.
Mitochondrial peroxiredoxin 3 (Prx 3) is rapidly oxidized in cells exposed to phenethyl isothiocyanate (PEITC) and auranofin (AFN), but the mechanism of oxidation is unclear. Using HL-60 cells deplete of mitochondrial DNA we show that peroxiredoxin 3 oxidation and cytotoxicity requires a functional respiratory chain. Thioredoxin reductase (TrxR) could be inhibited by up to 90% by auranofin without direct oxidation of peroxiredoxin 3. However, inhibition of thioredoxin reductase promoted peroxiredoxin 3 oxidation and cytotoxicity in combination with phenethyl isothiocyanate or antimycin A. We conclude that rapid peroxiredoxin 3 oxidation occurs as a consequence of increased oxidant production from the mitochondrial respiratory chain.
Brown
Kristin K
KK
National Research Centre for Growth and Development, Department of Pathology, University of Otago, Christchurch, New Zealand.
Cox
Andrew G
AG
Hampton
Mark B
MB
D000968:Antimycin A / Q000494:pharmacology; D001310:Auranofin / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction / Q000187:drug effects; D061105:Peroxiredoxin III; D054464:Peroxiredoxins / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D001310:Auranofin; D000968:Antimycin A; C058305:phenethyl isothiocyanate; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D013880:Thioredoxin-Disulfide Reductase