Energy thresholds in brain mitochondria - Potential involvement in neurodegeneration
Energy thresholds in brain mitochondria - Potential involvement in neurodegeneration
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DOI：
10.1074/jbc.273.21.12753
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发表时间：
1998-05-22
影响因子：
4.8
通讯作者：
Clark, JB
中科院分区：
文献类型：
--
作者：
Davey, GP;Peuchen, S;Clark, JB
线粒体呼吸链复合物活动的减少与神经退行性疾病（如帕金森病、亨廷顿病和阿尔茨海默病）有关，然而，这些减少在多大程度上引起大脑氧化磷酸化和能量稳态的紊乱尚不清楚。因此，我们研究了单个线粒体呼吸链复合物对突触线粒体nadd连接的底物氧化磷酸化控制的相对贡献。用特定抑制剂滴定复合物I、III和IV的活性，产生阈值曲线，显示复合物活性在引起线粒体能量代谢损伤之前可以被抑制的程度。复合物I、III和TV活性分别下降了约25%、80%和70%，然后才观察到氧气消耗率和ATP合成率发生了重大变化。这些结果表明，在突触起源的线粒体中，复合物I的活性主要控制氧化磷酸化，因此当超过25%的抑制阈值时，能量代谢严重受损，导致ATP合成减少。此外，据报道，谷胱甘肽的消耗是特发性帕金森病的主要事件，它消除了PC12细胞中的复合物I阈值，这表明抗氧化状态在维持线粒体的能量阈值方面很重要。这些发现的意义讨论了神经退行性疾病和能量代谢在突触。
Decreases in mitochondrial respiratory chain complex activities have been implicated in neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and Alzheimer's disease, However, the extent to which these decreases cause a disturbance in oxidative phosphorylation and energy homeostasis in the brain is not known. We therefore examined the relative contribution of individual mitochondrial respiratory chain complexes to the control of NAD-linked substrate oxidative phosphorylation in synaptic mitochondria. Titration of complex I, III, and IV activities with specific inhibitors generated threshold curves that showed the extent to which a complex activity could be inhibited before causing impairment of mitochondrial energy metabolism. Complex I, III, and TV activities were decreased by approximately 25, 80, and 70%, respectively, before major changes in rates of oxygen consumption and ATP synthesis mere observed. These results suggest that, in mitochondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25% inhibition is exceeded, energy metabolism is severely impaired, resulting in a reduced synthesis of ATP. Additionally, depletion of glutathione, which has been reported to be a primary event in idiopathic Parkinson's disease, eliminated the complex I threshold in PC12 cells, suggesting that antioxidant status is important in maintaining energy thresholds in mitochondria. The implications of these findings are discussed with respect to neurodegenerative disorders and energy metabolism in the synapse.