Early developmental pathology due to cytochrome c oxidase deficiency is revealed by a new zebrafish model
Early developmental pathology due to cytochrome c oxidase deficiency is revealed by a new zebrafish model
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DOI：
10.1074/jbc.m703528200
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发表时间：
2007-11-30
影响因子：
4.8
通讯作者：
Guillemin, Karen
中科院分区：
文献类型：
--
作者：
Baden, Katrina N.;Murray, James;Guillemin, Karen
细胞色素c氧化酶（考克斯）的缺乏与人类的显著病理学相关。然而，器官发生和早期发育的后果还没有得到很好的理解。我们使用斑马鱼模型研究了这些问题。考克斯缺陷是使用吗啉代来减少CoxVa（一种结构亚基）和Surf 1（一种组装因子）的表达而诱导的，这两种亚基都损害了考克斯组装。考克斯活性降低至50%导致内胚层组织、心脏功能和游泳行为的发育缺陷。细胞研究揭示了不同的潜在机制。中脑和神经管的凋亡显著增加，次级运动神经元缺失或异常，解释了运动缺陷。相比之下，心脏缺乏凋亡细胞，但随着时间的推移表现越来越差，与能量缺乏一致。斑马鱼模型揭示了对考克斯缺乏的组织特异性反应，并有望发现治疗人类线粒体疾病的新疗法。
Deficiency of cytochrome c oxidase (COX) is associated with significant pathology in humans. However, the consequences for organogenesis and early development are not well understood. We have investigated these issues using a zebrafish model. COX deficiency was induced using morpholinos to reduce expression of CoxVa, a structural subunit, and Surf1, an assembly factor, both of which impaired COX assembly. Reduction of COX activity to 50% resulted in developmental defects in endodermal tissue, cardiac function, and swimming behavior. Cellular investigations revealed different underlying mechanisms. Apoptosis was dramatically increased in the hindbrain and neural tube, and secondary motor neurons were absent or abnormal, explaining the motility defect. In contrast, the heart lacked apoptotic cells but showed increasingly poor performance over time, consistent with energy deficiency. The zebrafish model has revealed tissue-specific responses to COX deficiency and holds promise for discovery of new therapies to treat mitochondrial diseases in humans.