Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.
Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism.
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DOI：
10.1371/journal.pone.0190456
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Konradi C
中科院分区：
文献类型：
--
作者：
Warren EB;Aicher AE;Fessel JP;Konradi C
线粒体 DNA (mtDNA) 是编码线粒体呼吸链亚基的离散基因组，在不同细胞类型中存在高度可变的拷贝数。尽管严重的 mtDNA 耗竭会显着降低线粒体功能，但组织特异性 mtDNA 减少的影响仍然存在争议。此前，我们的实验室发现，与未发生 L-DOPA 诱发的运动障碍 (LID) 的帕金森病 (PD) 患者和健康受试者相比，其壳核中 mtDNA 数量减少。在这里，我们介绍了溴化乙锭 (EtBr) 处理去除 mtDNA 对原代培养的神经元、星形胶质细胞和来自大鼠纹状体的富含神经元的共培养物的生物能功能的影响。我们报告说，EtBr 对 mtDNA 复制和转录的抑制持续降低线粒体耗氧量，并且神经元对 EtBr 比星形胶质细胞更敏感。 EtBr 还会增加星形胶质细胞中的糖酵解活性，而在神经元中，它会降低线粒体肌酸激酶 mRNA 的表达和磷酸肌酸的水平。此外，我们发现，与非运动障碍性帕金森病患者和健康受试者相比，线粒体肌酸激酶 mRNA 在运动障碍性帕金森病患者中同样下调。我们的数据支持这样一种假设，即纹状体 mtDNA 的减少通过破坏磷酸肌酸/肌酸穿梭的能量缓冲系统的稳定性，导致运动障碍纹状体的能量失调。
Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson’s Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non-dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle.
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影响因子：
3.7
作者：
Damiano, Maria;Gautier, Clement A.;Lombes, Anne
通讯作者：
Lombes, Anne
DOI：
10.1146/annurev-genom-082509-141720
发表时间：
2010
影响因子：
8.7
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通讯作者：
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影响因子：
21.3
作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
通讯作者：
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影响因子：
6.7
作者：
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