2. Academic Validation
  3. IHG-1 increases mitochondrial fusion and bioenergetic function

IHG-1 increases mitochondrial fusion and bioenergetic function

  • Diabetes. 2014 Dec;63(12):4314-25. doi: 10.2337/db13-1256.
Fionnuala B Hickey 1,  James B Corcoran 2,  Brenda Griffin 3,  Una Bhreathnach 2,  Heather Mortiboys 4,  Helen M Reid 5,  Darrell Andrews 3,  Shane Byrne 3,  Fiona Furlong 6,  Finian Martin 3,  Catherine Godson 2,  Madeline Murphy 7
Affiliations

Affiliations

  • 1 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.
  • 2 Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
  • 3 Diabetes Complications Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
  • 4 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, U.K.
  • 5 School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
  • 6 School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland.
  • 7 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.
PMID: 25008184 DOI: 10.2337/db13-1256
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.

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