Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.
Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.
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DOI：
10.1093/hmg/ddr537
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发表时间：
2012-03
影响因子：
3.5
通讯作者：
F. Sterky;A. Hoffman;Dusanka Milenkovic;Betty Bao;A. Paganelli;Daniel Edgar;R. Wibom;C. Lupica;L. Olson;N. Larsson
中科院分区：
文献类型：
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作者：
F. Sterky;A. Hoffman;Dusanka Milenkovic;Betty Bao;A. Paganelli;Daniel Edgar;R. Wibom;C. Lupica;L. Olson;N. Larsson
多种观察结果支持这样的假设：线粒体呼吸链复合物 I [还原型烟酰胺腺嘌呤二核苷酸 (NADH)：泛醌氧化还原酶] 的缺乏在帕金森病 (PD) 的病理生理学中发挥作用。然而，最近一项使用敲除复合物 I 亚基 NADH：泛醌氧化还原酶铁硫蛋白 4 (Ndufs4) 的小鼠进行的研究数据对这一概念提出了挑战，因为这些小鼠表现出非多巴胺神经元的退化。此外，据报道，源自此类小鼠的初级多巴胺 (DA) 神经元缺乏复合物 I 活性，但对据信通过抑制复合物 I 发挥作用的毒素仍然敏感。我们对小鼠心脏中的 Ndufs4 基因进行组织特异性破坏，发现在破坏的线粒体中复合物 I 活性明显严重缺乏，而导致复合物 I 水平的电子进入的底物氧化在完整的分离心脏线粒体中仅轻度减少。对去污剂溶解的线粒体的进一步分析表明，突变复合物 I 不稳定，但能够形成具有复合物 I 酶活性的超级复合物。因此，Ndufs4 的缺失仅导致体内复合物 I 轻度缺乏。我们继续破坏中脑 DA 神经元中的 Ndufs4，发现在组织特异性敲除动物中没有明显的神经变性，没有纹状体神经支配的丧失，也没有帕金森病的症状。然而，DA 稳态异常，DA 释放受损，DA 代谢物水平升高。此外，Ndufs4 DA 神经元敲除更容易受到神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶的影响。总而言之，这些发现在体内支持了复合物 I 缺乏可能导致 PD 病理生理学的假设。
A variety of observations support the hypothesis that deficiency of complex I [reduced nicotinamide-adenine dinucleotide (NADH):ubiquinone oxidoreductase] of the mitochondrial respiratory chain plays a role in the pathophysiology of Parkinson's disease (PD). However, recent data from a study using mice with knockout of the complex I subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) has challenged this concept as these mice show degeneration of non-dopamine neurons. In addition, primary dopamine (DA) neurons derived from such mice, reported to lack complex I activity, remain sensitive to toxins believed to act through inhibition of complex I. We tissue-specifically disrupted the Ndufs4 gene in mouse heart and found an apparent severe deficiency of complex I activity in disrupted mitochondria, whereas oxidation of substrates that result in entry of electrons at the level of complex I was only mildly reduced in intact isolated heart mitochondria. Further analyses of detergent-solubilized mitochondria showed the mutant complex I to be unstable but capable of forming supercomplexes with complex I enzyme activity. The loss of Ndufs4 thus causes only a mild complex I deficiency in vivo. We proceeded to disrupt Ndufs4 in midbrain DA neurons and found no overt neurodegeneration, no loss of striatal innervation and no symptoms of Parkinsonism in tissue-specific knockout animals. However, DA homeostasis was abnormal with impaired DA release and increased levels of DA metabolites. Furthermore, Ndufs4 DA neuron knockouts were more vulnerable to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Taken together, these findings lend in vivo support to the hypothesis that complex I deficiency can contribute to the pathophysiology of PD.