IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses

Biochim Biophys Acta. 2013 Aug;1833(8):1969-78. doi: 10.1016/j.bbamcr.2013.03.027. Epub 2013 Apr 6.


TGF-β1 is a prototypic profibrotic cytokine and major driver of fibrosis in the kidney and other organs. Induced in high glucose-1 (IHG-1) is a mitochondrial protein which we have recently reported to be associated with renal disease. IHG-1 amplifies responses to TGF-β1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localisation of IHG-1 is pivotal in the amplification of TGF-β1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-β1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Δmts-IHG-1) repressed TGF-β1 fibrotic signalling in renal epithelial cells. In cells expressing Δmts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-β1. Δmts-IHG-1 modulation of TGF-β1 signalling was associated with increased Smad7 protein expression. Δmts-IHG-1 modulated TGF-β1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-β1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-β1 signal transduction and that IHG-1 is a key player in this modulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Line
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Epithelial Cells / metabolism
  • Fibronectins / genetics
  • Fibronectins / metabolism
  • Fibrosis / genetics
  • Fibrosis / metabolism*
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Kidney / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Smad7 Protein / biosynthesis*
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*


  • CCN2 protein, human
  • Calcium-Binding Proteins
  • Fibronectins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • Proteins
  • SMAD7 protein, human
  • Serrate-Jagged Proteins
  • Smad7 Protein
  • THG1L protein, human
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor