Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function.
Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function.
复制标题
小鼠 Idh3a 突变导致视网膜变性和线粒体功能降低。
DOI：
10.1242/dmm.036426
复制
发表时间：
2018-12-18
影响因子：
4.3
通讯作者：
Jackson IJ
中科院分区：
文献类型：
--
作者：
Findlay AS;Carter RN;Starbuck B;McKie L;Nováková K;Budd PS;Keighren MA;Marsh JA;Cross SH;Simon MM;Potter PK;Morton NM;Jackson IJ
异柠檬酸脱氢酶(IDH)是由异柠檬酸合成α-酮戊二酸所必需的酶。IDH3产生线粒体中用于产生三磷酸腺苷的NADH，是一个由两个α、一个β和一个γ亚基组成的四聚体。IDH3A和IDH3B的功能丧失和错义突变以前曾被认为与表现出视网膜变性的家族有关。利用小鼠模型，我们研究了IDH3在视网膜疾病和线粒体功能中的作用。我们在一组携带ENU诱导的Idh3a突变E229K的老年小鼠中发现了迟发性视网膜变性的小鼠。这种突变纯合子的小鼠早在3个 月时就表现出视网膜应激的迹象，由胶质纤维酸性蛋白染色显示，但其他组织似乎没有受到影响。我们进行了Idh3a基因敲除，发现纯合子小鼠在早期胚胎发育后无法存活。Idh3a−/E229K复合杂合突变株较Idh3aE229K/E229K纯合突变株表现出更严重的视网膜变性。对突变细胞系线粒体功能的分析表明，在Idh3a E229K/E229K和Idh3a−/E229K细胞中，线粒体最大呼吸和储备能力水平都有所降低。功能丧失的Idh3b突变体没有表现出相同的视网膜变性表型，没有视网膜应激或线粒体呼吸减少的迹象。此前已有报道称，视网膜的线粒体储备能力有限，我们认为，这一点与突变体中储备能力的降低结合在一起，解释了在Idh3a突变小鼠中观察到的退行性表型。摘要：在这里，我们展示了IDH3a基因的部分功能缺失突变会由于线粒体功能受损而导致视网膜变性。然而，完全丧失Idh3a在胚胎上是致命的。
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. 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.
登录
查看更多内容
影响因子：
5.6
作者：
Guerois, R;Nielsen, JE;Serrano, L
通讯作者：
Serrano, L
影响因子：
2.9
作者：
Bzymek, Krzysztof P.;Colman, Roberta F.
通讯作者：
Colman, Roberta F.
DOI：
10.1016/s0925-4439(97)00035-5
发表时间：
1997-08-22
影响因子：
6.2
作者：
Rustin, P;Bourgeron, T;Rotig, A
通讯作者：
Rotig, A
影响因子：
13.7
作者：
Pierrache LHM;Kimchi A;Ratnapriya R;Roberts L;Astuti GDN;Obolensky A;Beryozkin A;Tjon-Fo-Sang MJH;Schuil J;Klaver CCW;Bongers EMHF;Haer-Wigman L;Schalij N;Breuning MH;Fischer GM;Banin E;Ramesar RS;Swaroop A;van den Born LI;Sharon D;Cremers FPM
通讯作者：
Cremers FPM
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya