Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function

Isocitrate 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 and have previ...

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Published inDisease models & mechanisms Vol. 11; no. 12
Main Authors Findlay, Amy S, Carter, Roderick N, Starbuck, Becky, McKie, Lisa, Nováková, Klára, Budd, Peter S, Keighren, Margaret A, Marsh, Joseph A, Cross, Sally H, Simon, Michelle M, Potter, Paul K, Morton, Nicholas M, Jackson, Ian J
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Abstract Isocitrate 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 and 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 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 and found that homozygous mice do not survive past early embryogenesis. compound heterozygous mutants exhibit a more severe retinal degeneration compared with homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both and cells. Loss-of-function 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 mutant mice.This article has an associated First Person interview with the first author of the paper.
AbstractList Isocitrate 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, a β and a γ subunit. Loss of function and missense mutations in both IDH3A andIDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models we have 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 when compared to Idh3aE229K/E229K. 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 been previously 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.
Isocitrate 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.
Isocitrate 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 Idh3a E229K/E229K homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3a E229K/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. Summary: Here, we show that partial loss-of-function mutations in the Idh3a gene lead to retinal degeneration due to compromised mitochondrial function. Complete loss of Idh3a , however, is embryonically lethal.
Isocitrate 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 and 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 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 and found that homozygous mice do not survive past early embryogenesis. compound heterozygous mutants exhibit a more severe retinal degeneration compared with homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both and cells. Loss-of-function 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 mutant mice.This article has an associated First Person interview with the first author of the paper.
Author Cross, Sally H
Morton, Nicholas M
Marsh, Joseph A
Carter, Roderick N
Potter, Paul K
Jackson, Ian J
Nováková, Klára
Keighren, Margaret A
Simon, Michelle M
Starbuck, Becky
McKie, Lisa
Findlay, Amy S
Budd, Peter S
AuthorAffiliation 3 MRC Mammalian Genetics Unit , MRC Harwell Institute , Harwell Campus, Oxfordshire OX11 0RD , UK
4 Roslin Institute, University of Edinburgh , Edinburgh EH25 9RG , UK
2 Molecular Metabolism Group , Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh , Edinburgh EH16 4TJ , UK
1 MRC Human Genetics Unit , Institute of Genetics and Molecular Medicine, University of Edinburgh , Crewe Road, Edinburgh EH4 2XU , UK
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Issue 12
Keywords Retinitis pigmentosa
Mouse model
Krebs cycle
Language English
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Snippet Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria...
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pubmedcentral
proquest
crossref
pubmed
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
SubjectTerms Age
Animals
Dehydrogenases
Disease
Fibroblasts - metabolism
Genes
Genotype
Genotype & phenotype
Isocitrate Dehydrogenase - genetics
Isocitrate Dehydrogenase - metabolism
Krebs cycle
Loss of Function Mutation - genetics
Mice
Mitochondria
Mitochondria - pathology
Mouse model
Mutation
Mutation - genetics
Mutation, Missense - genetics
Patients
Phenotype
Photoreceptor Cells, Vertebrate - metabolism
Photoreceptor Cells, Vertebrate - pathology
Proteins
Retina
Retina - pathology
Retina - physiopathology
Retinal Degeneration - genetics
Retinal Degeneration - physiopathology
Retinitis pigmentosa
Tumors
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Title Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function
URI https://www.ncbi.nlm.nih.gov/pubmed/30478029
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Volume 11
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