Alternative oxidase rescues mitochondria-mediated dopaminergic cell loss in Drosophila
Alternative oxidase rescues mitochondria-mediated dopaminergic cell loss in Drosophila
复制标题
DOI：
10.1093/hmg/dds096
复制
发表时间：
2012-06-15
影响因子：
3.5
通讯作者：
Hirth, Frank
中科院分区：
文献类型：
--
作者：
Humphrey, Dickon M.;Parsons, Richard B.;Hirth, Frank
线粒体功能障碍通常在退行性疾病中观察到，包括阿尔茨海默病和帕金森病，其特征在于神经元亚群的进行性和选择性丧失。然而，目前尚不清楚线粒体功能障碍是原发性的还是继发于最终导致年龄相关性神经变性的其他致病过程。在这里，我们建立了一个在体内果蝇模型的线粒体功能障碍，通过下调线粒体DNA（mtDNA）聚合酶的催化亚基在胆碱能，多巴胺能和多巴胺能神经元。由此产生的果蝇的特征在于降低的呼吸链活性、过早衰老、与年龄相关的运动缺陷以及成年发病、进行性和细胞类型特异性的多巴胺能神经变性。使用这个模型，我们发现相关的致死性可以通过靶向PINK 1/parkin信号传导或Drp 1来部分挽救，这两者都与线粒体动力学和帕金森病有关。然而，用替代氧化酶（AOX）消除线粒体复合物III/IV缺陷，完全恢复ATP水平并防止多巴胺能神经变性。相比之下，ATP水平和神经退行性变时，线粒体复合物I的缺陷，绕过NADH-Q氧化还原酶没有获救。我们的研究结果表明，mtDNA介导的线粒体功能障碍可以导致年龄相关的和细胞类型特异性的神经退行性变，AOX能够减轻，并表明AOX或其替代物可能被证明是一种有用的治疗工具，用于限制健康衰老和神经退行性疾病中mtDNA下降引起的呼吸链缺陷。
Mitochondrial dysfunction is commonly observed in degenerative disorders, including Alzheimers and Parkinsons disease that are characterized by the progressive and selective loss of neuronal subpopulations. It is currently unclear, however, whether mitochondrial dysfunction is primary or secondary to other pathogenic processes that eventually lead to age-related neurodegeneration. Here we establish an in vivo Drosophila model of mitochondrial dysfunction by downregulating the catalytic subunit of mitochondrial DNA (mtDNA) polymerase in cholinergic, serotonergic and dopaminergic neurons. The resulting flies are characterized by lowered respiratory chain activity, premature aging, age-related motor deficits as well as adult onset, progressive and cell-type-specific, dopaminergic neurodegeneration. Using this model, we find that associated lethality can be partially rescued by targeting PINK1/parkin signaling or Drp1, both of which have been implicated in mitochondrial dynamics and Parkinsons disease. Bypassing mitochondrial complex III/IV deficiencies with Alternative oxidase (AOX), however, fully restores ATP levels and prevents dopaminergic neurodegeneration. In contrast, ATP levels and neurodegeneration are not rescued when mitochondrial complex I deficiencies are bypassed with NADH-Q oxidoreductase. Our results demonstrate that mtDNA-mediated mitochondrial dysfunction can cause age-related and cell-type-specific neurodegeneration which AOX is able to alleviate and indicate that AOX or its surrogates may prove useful as a therapeutic tool for limiting respiratory chain deficiencies caused by mtDNA decline in healthy aging and neurodegenerative disease.