IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1α

Increased expression of Induced-by-High-Glucose 1 (IHG-1) associates with tubulointerstitial fibrosis in diabetic nephropathy. IHG-1 amplifies TGF-?1 signaling, but the functions of this highly-conserved protein are not well understood. IHG-1 contains a putative mitochondrial-localization domain, and here we report that IHG-1 is specifically localized to mitochondria. IHG-1 overexpression increased mitochondrial mass and stabilized peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?). Conversely, inhibition of IHG-1 expression decreased mitochondrial mass, downregulated mitochondrial proteins, and PGC-1?-regulated transcription factors, including nuclear respiratory factor 1 and mitochondrial transcription factor A (TFAM), and reduced activity of the TFAM promoter. In the unilateral ureteral obstruction model, we observed higher PGC-1? protein expression and IHG-1 levels with fibrosis. In a gene-expression database, we noted that renal biopsies of human diabetic nephropathy demonstrated higher expression of genes encoding key mitochondrial proteins, including cytochrome c and manganese superoxide dismutase, compared with control biopsies. In summary, these data suggest that IHG-1 increases mitochondrial biogenesis by promoting PGC-1?-dependent processes, potentially contributing to the pathogenesis of renal fibrosis

The book of dissertations by third year students of SAUL University of Limerick 2009-2010

The book of dissertations by third year students of SAUL University of Limerick 2009-201

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

AbstractTGF-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

Supplementary_material – Supplemental material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer

<p>Supplemental material, Supplementary_material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer by Naomi Elster, Sinead Toomey, Yue Fan, Mattia Cremona, Clare Morgan, Karolina Weiner Gorzel, Una Bhreathnach, Malgorzata Milewska, Madeline Murphy, Stephen Madden, Jarushka Naidoo, Joanna Fay, Elaine Kay, Aoife Carr, Sean Kennedy, Simon Furney, Janusz Mezynski, Oscar Breathhnach, Patrick Morris, Liam Grogan, Arnold Hill, Susan Kennedy, John Crown, William Gallagher, Bryan Hennessy and Alex Eustace in Therapeutic Advances in Medical Oncology</p