Thioredoxin reductase-2 is essential for keeping low levels of H 2O 2 emission from isolated heart mitochondria

Brian A. Stanley, Vidhya Sivakumaran, Sa Shi, Iain McDonald, David Lloyd, Walter H. Watson, Miguel A. Aon, Nazareno Paolocci

Research output: Contribution to journalArticlepeer-review

Abstract

Respiring mitochondria produce H 2O 2 continuously. When production exceeds scavenging, H 2O 2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H 2O 2 to water using reducing equivalents from NADPH supplied by thioredoxin-2 (Trx2) and, ultimately, thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial thioredoxin system to the control of H 2O 2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H 2O 2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H 2O 2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H 2O 2 emission through a mechanism that is independent of changes in other redox couples.

Original languageEnglish (US)
Pages (from-to)33669-33677
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number38
DOIs
StatePublished - Sep 23 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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