Abstract
ABSTRACTIsocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both IDH3A and IDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models, we investigated the role of IDH3 in retinal disease and mitochondrial function. We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a. Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of Idh3a and found that homozygous mice do not survive past early embryogenesis. Idh3a−/E229K compound heterozygous mutants exhibit a more severe retinal degeneration compared with Idh3aE229K/E229K homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3aE229K/E229K and Idh3a−/E229K cells. Loss-of-function Idh3b mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration. It has previously been reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in Idh3a mutant mice.This article has an associated First Person interview with the first author of the paper.
Highlights
We have identified a missense mutation in the gene encoding a subunit of the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase 3 (IDH3) as causing a retinal degeneration phenotype in mice
Mitochondria show a reduced maximal and reserve capacity As IDH3 is an essential part of the mitochondrial TCA cycle, we investigated how the Idh3a mutations affected the overall function of mitochondria (Fig. 4A)
This is the first mouse model of IDH3A-related chronic retinal degeneration described, and closely mirrors the phenotype observed in patients
Summary
Mitochondrial diseases are highly diverse: over 220 different genes have been identified that can cause diseases of the mitochondria, and. Common to many of the diseases, are neurological or neuromuscular manifestations, including retinal disease. We have identified a missense mutation in the gene encoding a subunit of the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase 3 (IDH3) as causing a retinal degeneration phenotype in mice. No inherited disease has been associated with IDH1 mutations, but mutations in IDH2 cause a metabolic disease, D-2hydroxyglutaric aciduria, with a range of features including epilepsy, hypotonia and other neurological manifestations (Kranendijk et al, 2010). IDH3 is located in the mitochondria, where the conversion of isocitrate to α-ketoglutarate is necessary for the TCA cycle to progress and generate NADH, which feeds into oxidative phosphorylation to generate ATP. No recurrent mutations in any of the IDH3 genes have been described in tumours
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
