Uncoupling of the Electron Transport Chain Compromises Mitochondrial Oxidative Phosphorylation and Exacerbates Stroke Outcomes.
Uncoupling of the Electron Transport Chain Compromises Mitochondrial Oxidative Phosphorylation and Exacerbates Stroke Outcomes.
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DOI：
10.4172/2314-7326.1000283
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Ren, Xuefang
中科院分区：
文献类型：
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作者：
Grasmick, Kimberly A;Hu, Heng;Ren, Xuefang
目的：线粒体功能障碍与中风有关，但中风的复杂机制导致中风治疗很少。本研究通过已知的电子传递链（ETC）解偶联剂羰基氰-4（三氟甲氧基）苯腙（FCCP）破坏线粒体氧化磷酸化。分析由此产生的神经功能缺损以及梗死体积可以帮助确定线粒体在卒中结局中的作用，并确定将ETC解偶联是否可能成为新的卒中治疗策略。本研究的目的是确定解偶联电子流对线粒体氧化磷酸化和中风infarct.METHODS的影响：脑血管内细胞（CEC）处理不同浓度的FCCP，并测定生物能量学。对于中风小鼠模型，给予FCCP（1 mg/kg，i.p）或溶剂，然后进行1小时短暂性大脑中动脉闭塞（tMCAO）。再灌注23小时后测量脑梗死体积，氯化三苯基四氮唑（TTC）染色用于评估梗死体积。结果：当FCCP浓度大于1000 nM时，FCCP显著降低基础呼吸、ATP周转、最大呼吸和备用容量。用FCCP预处理的小鼠在皮质、纹状体和整个半球内具有显著增加的梗死体积。接受FCCP的小鼠有一个显着增加的神经功能缺损评分相比vehicle.CONCLUSIONS：FCCP损害线粒体氧化磷酸化CEC在剂量依赖性的方式。在tMCAO之前将电子传递链与FCCP解偶联会加重小鼠的中风梗死。
OBJECTIVE: Mitochondrial dysfunction is known to be implicated in stroke, but the complex mechanisms of stroke have led to few stroke therapies. The present study to disrupted mitochondrial oxidative phosphorylation through a known electron transport chain (ETC) uncoupler, Carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP). Analyzing the resulting neurological deficits as well as infarct volume could help determine the role of mitochondria in stroke outcome and determine whether uncoupling the ETC could potentially be a strategy for new stroke therapies. The objective of this study was to determine the effects of uncoupling electron flow on mitochondrial oxidative phosphorylation and stroke infarction.METHODS: Cerebral endovascular cells (CECs) were treated with various concentrations of FCCP, and bioenergetics were measured. For the stroke mouse model, FCCP (1 mg/kg, i.p) or vehicle was administered followed by 1-hour transient middle cerebral artery occlusion (tMCAO). Infarct volume was measured after a 23-hour reperfusion, and triphenyl tetrazolium chloride (TTC) staining was used to assess infarct volume.RESULTS: FCCP significantly decreased basal respiration, ATP turnover, maximal respiration, and spare capacity when the concentration of FCCP was greater than 1000 nM. The mice pretreated with FCCP had a significantly increased infarct volume within the cortex, striatum, and total hemisphere. Mice receiving FCCP had a significantly increased neurological deficit score compared to the vehicle.CONCLUSIONS: FCCP compromised mitochondrial oxidative phosphorylation in CECs in a dose-dependent manner. Uncoupling the electron transport chain with FCCP prior to tMCAO exacerbated stroke infarction in mice.