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

TGF-beta 1 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-beta 1 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-beta 1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-beta 1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Delta mts-IHG-1) repressed TGF-beta 1 fibrotic signalling in renal epithelial cells. In cells expressing Delta mts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-beta 1. Delta mts-IHG-1 modulation of TGF-beta 1 signalling was associated with increased Smad7 protein expression. Delta mts-IHG-1 modulated TGF-beta 1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-beta 1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-beta 1 signal transduction and that IHG-1 is a key player in this modulation. (C) 2013 Elsevier B.V. All rights reserved.