Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling

Manu Jain*, Stephanie Rivera, Elena A. Monclus, Lauren Synenki, Aaron Zirk, James Eisenbart, Carol Feghali-Bostwick, Gokhan M. Mutlu, GR Scott Budinger, Navdeep Chandel

*Corresponding author for this work

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

TGF-β signaling is required for normal tissue repair; however, excessive TGF-β signaling can lead to robust profibrotic gene expression in fibroblasts, resulting in tissue fibrosis. TGF-β binds to cell-surface receptors, resulting in the phosphorylation of the Smad family of transcription factors to initiate gene expression. TGF-β also initiates Smad-independent pathways, which augment gene expression. Here, we report that mitochondrial reactive oxygen species (ROS) generated at complex III are required for TGF-β-induced gene expression in primary normal human lung fibroblasts. TGF-β-induced ROS could be detected in both the mitochondrial matrix and cytosol. Mitochondrially targeted antioxidants markedly attenuated TGF-β-induced gene expression without affecting Smad phosphorylation or nuclear translocation. Genetically disrupting mitochondrial complex III-generated ROS production attenuated TGF-β-induced profibrotic gene expression. Furthermore, inhibiting mitochondrial ROS generation attenuated NOX4 (NADPH oxidase 4) expression, which is required for TGF-β induced myofibroblast differentiation. Lung fibroblasts from patients with pulmonary fibrosis generated more mitochondrial ROS than normal human lung fibroblasts, and mitochondrially targeted antioxidants attenuated profibrotic gene expression in both normal and fibrotic lung fibroblasts. Collectively, our results indicate that mitochondrial ROS are essential for normal TGF-β-mediated gene expression and that targeting mitochondrial ROS might be beneficial in diseases associated with excessive fibrosis.

Original languageEnglish (US)
Pages (from-to)770-777
Number of pages8
JournalJournal of Biological Chemistry
Volume288
Issue number2
DOIs
StatePublished - Jan 11 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jain, M., Rivera, S., Monclus, E. A., Synenki, L., Zirk, A., Eisenbart, J., Feghali-Bostwick, C., Mutlu, G. M., Budinger, GR. S., & Chandel, N. (2013). Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. Journal of Biological Chemistry, 288(2), 770-777. https://doi.org/10.1074/jbc.M112.431973