title: IHG-1 increases mitochondrial fusion and bioenergetic function.
abstract: Induced in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic transforming growth factor (TGF)-β1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion-mitofusins (Mfns) 1 and 2-and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-β, leading to renal proximal tubule dedifferentiation, an important event in the pathogenesis of this devastating condition.
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland Trinity Health Kidney Centre, Trinity College, Dublin, Ireland.
authors.forename: Fionnuala B
authors.initials: FB
authors.lastname: Hickey
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: James B
authors.initials: JB
authors.lastname: Corcoran
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Brenda
authors.initials: B
authors.lastname: Griffin
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Una
authors.initials: U
authors.lastname: Bhreathnach
authors.affiliation: Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, U.K.
authors.forename: Heather
authors.initials: H
authors.lastname: Mortiboys
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Reid
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Darrell
authors.initials: D
authors.lastname: Andrews
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: Byrne
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Furlong
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland madeline.murphy@ucd.ie.
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
mesh_terms: D017209:Apoptosis / Q000235:genetics; D019069:Cell Respiration / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; C532028:THG1L protein, human; D053773:Transforming Growth Factor beta1; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human