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.

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay

“…The position of the GpGpC product corresponding to G −1 addition is indicated, along with the Pi that results from unreacted substrate within the mitochondria and to act as a guanine nucleotide exchange factor (GEF) for MFN2 thereby increasing mitochondrial fusion. Complete loss of THG1L was associated with a reduction in the amount of GTP bound to Mfn2 and with reduced mitochondrial fusion, marked reduction in mitochondrial connectivity, and individual mitochondria that were small and punctate in appearance [9]. Our patient's cells when under respiratory conditions behaved similarly; in contrast to the control cells, the patients mitochondria were not elongated, were concentrated around the nuclei, and the mitochondrial network did not extend out, all indicative of impaired mitochondrial fusion.…”

“…PGC-1α activity contributes to the enhancement of mitochondrial stress-related bioenergetic function [18]. Complete loss of THG1L results in a significant decrease of mitochondrial respiration and ATP production [9].…”

“…1a, b) but we focused on the p.V55A variant in the THG1L gene because it affected a highly conserved residue throughout evolution (Fig. 1c) and because of its putative role in mitochondrial biogenesis [9]. Furthermore, knockout mice for the ADAM19 suffer from severe heart valve defects [10].…”

“…Because inhibition of THG1L was previously reported to affect mitochondrial fusion [9], we set out to assess mitochondrial network in the patients cultured skin fibroblasts. Mitochondrial morphology assessed by imaging the fibroblasts with mitotracker revealed no obvious morphology defect in patient cells compared to control when cultured in glucose containing medium (Fig.…”

Mitochondrial energetics in the kidney

“…MFN2 overexpression decreased ROS production, decreased kidney volume and attenuated the pathological changes seen in the diabetic kidney 193 . Induced in high glucose 1 (IHG1; also known as THG1L) is another protein that is involved in mitochondrial fusion and has been shown to regulate mitochondrial dynamics and biogenesis in the diabetic kidney 194 . IHG1 can enhance the ability of MFN2 to bind to GTP and interacts directly with MFN2 to mediate fusion 194 .…”