Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency.
Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency.
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DOI：
10.1093/hmg/ddt601
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发表时间：
2014-04-15
影响因子：
3.5
通讯作者：
Jacobs HT
中科院分区：
文献类型：
--
作者：
Kemppainen KK;Rinne J;Sriram A;Lakanmaa M;Zeb A;Tuomela T;Popplestone A;Singh S;Sanz A;Rustin P;Jacobs HT
线粒体功能障碍是人类疾病的一个重要因素，从儿童全身性疾病到心肌病、缺血和神经变性。细胞色素氧化酶，线粒体呼吸链的末端酶，是一个常见的目标。低等真核生物具有替代性的非质子转运链酶，在呼吸应激或超负荷条件下为呼吸复合物I（单亚基还原的烟酰胺腺嘌呤二核苷酸转移酶，例如来自酵母的Ndi 1）或III + IV [替代性氧化酶（AOX）]提供非质子转运旁路。在以前的研究中，它表明，酵母Ndi1或玻璃海鞘AOX转移到果蝇能够克服毒素或部分敲低复合物I或IV产生的致死性。在这里，我们表明，AOX可以提供一个完整的或实质性的救援的一系列表型诱导的全球或组织特异性敲除不同的cIV亚基，包括催化所需的整体亚基，以及多聚化和组装所需的外围亚基。AOX也能够克服蛹的致死性产生的肌肉特异性敲低亚基CoVb，虽然获救的苍蝇寿命短，有运动缺陷。cIV基因敲除在神经元发育过程中并不致命，但产生了一个快速进展的运动和神经元敏感性表型，这是大大减轻AOX。Ndi 1的表达加剧了cIV敲低产生的神经元表型。Ndi1表达的基本cI亚基的地方产生了一个独特的残留表型的延迟发展，爆炸敏感性和雄性不育。这些发现证实了替代呼吸链酶作为对抗线粒体疾病的工具的潜在效用，同时指出其重要的局限性。
Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.
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影响因子：
29
作者：
Balsa, Eduardo;Marco, Ricardo;Antonio Enriquez, Jose
通讯作者：
Antonio Enriquez, Jose
影响因子：
3.5
作者：
Humphrey, Dickon M.;Parsons, Richard B.;Hirth, Frank
通讯作者：
Hirth, Frank
影响因子：
3.5
作者：
D'Aurelio, Marilena;Gajewski, Carl D.;Manfredi, Giovanni
通讯作者：
Manfredi, Giovanni
影响因子：
7.7
作者：
Hakkaart, GAJ;Dassa, EP;Rustin, P
通讯作者：
Rustin, P
影响因子：
9.8
作者：
Huigsloot, Merei;Nijtmans, Leo G.;Rodenburg, Richard J. T.
通讯作者：
Rodenburg, Richard J. T.