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 in | Disease models & mechanisms Vol. 11; no. 12 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
The Company of Biologists Ltd
01.12.2018
The Company of Biologists |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1754-8403 1754-8411 |
DOI: | 10.1242/dmm.036426 |