IHG-1 Increases Mitochondrial Fusion and Bioenergetic Function
- Fionnuala B. Hickey*,†,
- James B. Corcoran*,†,
- Brenda Griffin*,‡,
- Una Bhreathnach*,†,
- Heather Mortiboys#,
- Helen M. Reid‡,
- Darrell Andrews*,‡,
- Shane Byrne*,‡,
- Fiona Furlong§,
- Finian Martin*,‡,
- Catherine Godson*,†+ and
- Madeline Murphy*,†+⇑
- *Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
- †UCD School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
- ‡UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
- #Academic Neurology Unit, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
- §School of Pharmacy, QUB, Lisburn Road, Belfast BT9 7BL, Northern Ireland.
- +Both authors share equivalent seniority
- Corresponding Author: Madeline Murphy, E-mail:
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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