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

James B Corcoran, Sarah McCarthy, Brenda Griffin, Andrew Gaffney, Una Bhreathnach, Emma Börgeson, Fionnuala B Hickey, Neil G Docherty, Debra F Higgins, Fiona Furlong, Finian Martin, Catherine Godson, Madeline Murphy

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


TGF-ß1 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-ß1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localization of IHG-1 is pivotal in amplification of TGF-ß1 signaling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-ß1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (?mts-IHG-1) repressed TGF-ß1 fibrotic signaling in renal epithelial cells. In cells expressing ?mts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-ß1. ?mts-IHG-1 modulation of TGF-ß1 signaling was associated with increased Smad7 protein expression. ?mts-IHG-1 modulated TGF-ß1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-ß1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-ß1 signal transduction and that IHG-1 is a key player in this modulation.
Original languageEnglish
Pages (from-to)1969-1978
JournalBiochimica et biophysica acta
Issue number8
Publication statusPublished - 2013

Bibliographical note

Copyright © 2013 Elsevier B.V. All rights reserved.

Fingerprint Dive into the research topics of 'IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses'. Together they form a unique fingerprint.

Cite this