title: IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1α.
abstract: Increased expression of Induced-by-High-Glucose 1 (IHG-1) associates with tubulointerstitial fibrosis in diabetic nephropathy. IHG-1 amplifies TGF-β1 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 γ coactivator-1α (PGC-1α). Conversely, inhibition of IHG-1 expression decreased mitochondrial mass, downregulated mitochondrial proteins, and PGC-1α-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-1α 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-1α-dependent processes, potentially contributing to the pathogenesis of renal fibrosis.
authors.affiliation: UCD Diabetes Research Centre, UCD Conway Institute, Ireland.
authors.forename: Fionnuala B
authors.initials: FB
authors.lastname: Hickey
authors.forename: James B
authors.initials: JB
authors.lastname: Corcoran
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.forename: Brenda
authors.initials: B
authors.lastname: Griffin
authors.forename: Una
authors.initials: U
authors.lastname: Bhreathnach
authors.forename: Fiona
authors.initials: F
authors.lastname: Furlong
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
mesh_terms: D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004272:DNA, Mitochondrial; D006360:Heat-Shock Proteins; C561362:IHG-1 protein, rat; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011506:Proteins; D016601:RNA-Binding Proteins; C532028:THG1L protein, human; D014157:Transcription Factors; D005947:Glucose