The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals.
The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals.
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DOI：
10.1371/journal.pgen.1000022
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发表时间：
2008-02-29
期刊：
影响因子：
4.5
通讯作者：
van der Bliek, Alexander M.
中科院分区：
文献类型：
--
作者：
Kanazawa, Takayuki;Zappaterra, Mauro D.;Hasegawa, Ayako;Wright, Ashley P.;Newman-Smith, Erin D.;Buttle, Karolyn F.;McDonald, Kent;Mannella, Carmen A.;van der Bliek, Alexander M.
秀丽隐杆线虫的eat-3基因编码线粒体动力蛋白家族成员，与人类的Opa1和酵母的Mgm1同源。我们发现秀丽隐杆线虫eat-3位点的突变导致线粒体断裂，这与在酵母和哺乳动物细胞中观察到的突变表型一致。电镜显示，在eat-3突变体中，线粒体碎片的基质被内膜分隔开，提示线粒体内膜融合存在特定缺陷。此外，我们发现秀丽隐杆线虫eat-3突变体动物比其他线粒体裂变和融合蛋白缺陷的秀丽隐杆线虫更小，生长速度更慢，繁殖规模更小。尽管哺乳动物的Opa1具有抗凋亡作用，但典型秀丽隐杆线虫细胞死亡基因ced-3和ced-4的突变不会抑制eat-3突变体的缓慢生长和小巢型表型。相反，eat-3突变体的表型与氧化磷酸化缺陷一致。此外，eat-3突变体对促进自由基损伤的百草枯过敏，并且对线粒体超氧化物歧化酶sod-2的丢失敏感。我们得出结论，自由基有助于秀丽隐杆线虫eat-3突变体的病理。显性视萎缩是一种由视网膜神经节细胞变性引起的进行性眼病。DOA最常见的形式是由Opa1蛋白突变引起的。这种蛋白质是线粒体融合所必需的，它具有抗凋亡功能，并且是线粒体DNA分离所必需的。然而，很难理解为什么Opa1的突变会特别影响视网膜神经节细胞。我们使用线虫秀丽隐杆线虫作为模型来研究Opa1病理的潜在原因。秀丽隐杆线虫Opa1是由eat-3基因编码的。突变体是迟钝的，生长缓慢，保持小，有小巢。这些表型不受细胞死亡基因突变的抑制，这表明细胞凋亡与eat-3的发病机制无关。相反，eat-3突变体对百草枯过敏，这会促进自由基的损伤，它们对线粒体超氧化物歧化酶sod-2的丧失敏感，而sod-2是消除线粒体基质中的自由基所必需的。此外，eat-3突变体过表达SOD-2，很可能补偿了自由基产生的增加。这些结果表明，秀丽隐杆线虫EAT-3在抵抗自由基中起重要作用，并提出了自由基与人类DOA有关的可能性。
The C. elegans eat-3 gene encodes a mitochondrial dynamin family member homologous to Opa1 in humans and Mgm1 in yeast. We find that mutations in the C. elegans eat-3 locus cause mitochondria to fragment in agreement with the mutant phenotypes observed in yeast and mammalian cells. Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane. In addition, we find that C. elegans eat-3 mutant animals are smaller, grow slower, and have smaller broodsizes than C. elegans mutants with defects in other mitochondrial fission and fusion proteins. Although mammalian Opa1 is antiapoptotic, mutations in the canonical C. elegans cell death genes ced-3 and ced-4 do not suppress the slow growth and small broodsize phenotypes of eat-3 mutants. Instead, the phenotypes of eat-3 mutants are consistent with defects in oxidative phosphorylation. Moreover, eat-3 mutants are hypersensitive to paraquat, which promotes damage by free radicals, and they are sensitive to loss of the mitochondrial superoxide dismutase sod-2. We conclude that free radicals contribute to the pathology of C. elegans eat-3 mutants. Dominant Optic Atrophy is a progressive eye disease caused by degeneration of retinal ganglion cells. The most prevalent form of DOA is caused by mutations in the Opa1 protein. This protein is required for fusion between mitochondria, it has an anti-apoptotic function, and it is required for mitochondrial DNA segregation. It has, nevertheless, been difficult to understand why mutations in Opa1 specifically affect retinal ganglion cells. We used rhe nematode C. elegans as a model to study the underlying causes of Opa1 pathologies. C. elegans Opa1 is encoded by the eat-3 gene. Mutants are sluggish, grow slowly, remain small, and have small broodsizes. These phenotypes are not suppressed by mutations in cell death genes, suggesting that apoptosis does not contribute to eat-3 pathogenesis. Instead, eat-3 mutants are hypersensitive to paraquat, which promotes damage by free radicals, and they are sensitive to loss of the mitochondrial superoxide dismutase sod-2, which is needed to eliminate free radicals from the mitochondrial matrix. Moreover, eat-3 mutants overexpress SOD-2, most likely compensating for increased free radical production. These results show that C. elegans EAT-3 is important for resistance to free radicals and they raise the possibility that free radicals contribute to DOA in humans.
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影响因子：
21.3
作者：
Bleazard, W;McCaffery, JM;Shaw, JM
通讯作者：
Shaw, JM
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
7.8
作者：
Hermann, G J;Thatcher, J W;Mills, J P;Hales, K G;Fuller, M T;Nunnari, J;Shaw, J M
通讯作者：
Shaw, J M
影响因子：
9.9
作者：
Kim, JY;Hwang, JM;Park, SS
通讯作者：
Park, SS
影响因子：
7.8
作者：
Ingerman, Elena;Perkins, Edward M;Marino, Michael;Mears, Jason A;McCaffery, J Michael;Hinshaw, Jenny E;Nunnari, Jodi
通讯作者：
Nunnari, Jodi