Thioredoxin1 upregulates mitochondrial proteins related to oxidative phosphorylation and TCA cycle in the heart

Tetsuro Ago, Ijen Yeh, Mitsutaka Yamamoto, Martina Schinke-Braun, Jeffrey A. Brown, Bin Tian, Junichi Sadoshima

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Abstract

Thioredoxin1 (Trx1) inhibits hypertrophy and exhibits protective functions in the heart. To elucidate further the cardiac functions of Trx1, we used a DNA microarray analysis, with hearts from transgenic mice with cardiac-specific overexpression of Trx1 (Tg-Trx1, n = 4) and nontransgenic controls (n = 4). Expression of a large number of genes is regulated in Tg-Trx1, with a greater number of genes downregulated, versus upregulated, at high-fold changes. The peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene was among the top 50 significantly upregulated genes. By pathway analyses, we found that genes involved in both mitochondrial oxidative phosphorylation and the TCA cycle were upregulated in Tg-Trx1. We confirmed up-regulation of cytochrome c oxidase (COX) components and mitochondrial transcription factor A in Tg-Trx1. The activity of citrate synthase and COX and the cardiac ATP content were significantly higher in Tg-Trx1. A transcription factor binding-site analysis showed that upregulated genes frequently contained binding sites for nuclear respiratory factor 1 (NRF1). Expression of NRF1 and PGC-1α was upregulated in Tg-Trx1, and Trx1 stimulated the transcriptional activity of NRF1 and NRF2 in cardiac myocytes. These results suggest that, in cardiac myocytes, Trx1 upregulates mitochondrial proteins and enhances mitochondrial functions, possibly through PGC-1α and NRFs.

Original languageEnglish
Pages (from-to)1635-1649
Number of pages15
JournalAntioxidants and Redox Signaling
Volume8
Issue number9-10
DOIs
Publication statusPublished - Sep 1 2006
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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