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.
- © 2014 by the American Diabetes Association.
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