IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function

  1. Madeline Murphy*,+
  1. *Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
  2. UCD School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
  3. UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
  4. #Academic Neurology Unit, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
  5. §School of Pharmacy, QUB, Lisburn Road, Belfast BT9 7BL, Northern Ireland.
  6. +Both authors share equivalent seniority
  1. Corresponding Author: Madeline Murphy, E-mail: madeline.murphy{at}


Increased in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic 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 – mitofusin 1 (Mfn1) and Mfn2, and enhances the GTP-binding capacity of Mfn2 suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localised 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

  • Received August 15, 2013.
  • Accepted July 2, 2014.

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