Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease
Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease
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DOI：
10.1111/j.1471-4159.2007.04996.x
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Usha, Rajamma
中科院分区：
文献类型：
--
作者：
Pandey, Mritunjay;Varghese, Merina;Usha, Rajamma
在亨廷顿病（HD）患者中观察到线粒体复合物-I功能障碍。我们评估了这种缺陷是否存在于HD的3-硝基丙酸（3-NP）模型中。用3-NP（10-20 mg/kg i.p.，4天）表现出体重减轻、步态异常和纹状体病变，在第5天和第9天神经胶质酸性蛋白免疫染色增加，而在治疗后第5天观察到纹状体多巴胺增加和酪氨酸羟化酶免疫反应性丧失。我们报告的第一次剂量依赖性减少复杂的-I在大脑皮层的活动时，分析荧光定量和蓝色天然聚丙烯酰胺凝胶电泳后3-NP治疗。柠檬酸合酶的线粒体复合物-I，-II，-（I + III）和-IV的标准化活动在3-NP处理的大鼠的皮质中降低。此外，琥珀酸驱动的状态3呼吸在体内和分离的线粒体中也被显著抑制。这些发现与NAD（+）-连接底物的状态3呼吸在体内而非体外显著降低的观察结果一起表明，除了复合物-II和琥珀酸脱氢酶活性的不可逆抑制之外，复合物-I功能障碍是3-NP-诱导的皮质-纹状体损伤的促成因素。
Mitochondrial complex-I dysfunction has been observed in patients of Huntington's disease (HD). We assessed whether such a defect is present in the 3-nitropropionic acid (3-NP) model of HD. Rats treated with 3-NP (10-20 mg/kg i.p., for 4 days) exhibited weight loss, gait abnormalities, and striatal lesions with increased glial fibrillary acidic protein immunostaining on fifth and ninth days, while increase in striatal dopamine and loss of tyrosine hydroxylase immunoreactivity were observed on fifth day following treatment. We report for the first time a dose-dependent reduction in complex-I activity in the cerebral cortex when analyzed spectrophotometrically and by blue native-polyacrylamide gel electrophoresis following 3-NP treatment. The citrate synthase normalized activities of mitochondrial complex-I, -II, -(I + III) and -IV were decreased in the cortex of 3-NP treated rats. In addition, succinate driven State 3 respiration was also significantly inhibited in vivo and in the isolated mitochondria. These findings taken together with the observation of a significant decrease in vivo but not in vitro of State 3 respiration with NAD(+)-linked substrates, suggest complex-I dysfunction in addition to irreversible inhibition of complex-II and succinate dehydrogenase activity as a contributing factor in 3-NP-induced cortico-striatal lesion.