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Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria
Neurochemistry international ( IF 4.2 ) Pub Date : 2017-10-16 , DOI: 10.1016/j.neuint.2017.10.003
Alexander Andreyev , Pratistha Tamrakar , Robert E. Rosenthal , Gary Fiskum

At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.



中文翻译:

正常和缺血性脑线粒体的钙摄取和细胞色素c释放

在细胞内Ca 2+含量异常升高的情况下,线粒体Ca 2+的吸收可能会损害线粒体的电子转运活性并触发膜通透性变化,从而使细胞色素c和其他线粒体凋亡蛋白释放到细胞质中。在这项研究中,使用临床相关的犬心脏骤停模型评估整体脑缺血和再灌注对线粒体Ca 2+摄取能力,Ca 2+摄取介导的呼吸抑制以及Ca 2+诱导的细胞色素c释放的影响。 ,在存在镁的情况下,在基于K +的培养基中进行体外测量2+,ATP和NADH连接的可氧化底物。与非缺血性对照组相比,心脏骤停后10分钟,额叶皮质线粒体的最大Ca 2+吸收量显着降低。来自缺血性脑的线粒体对与大量Ca 2+积累相关的呼吸抑制也更敏感。与非缺血性Shams的线粒体相比,细胞色素c在体外以Ca 2+剂量依赖性的方式从脑线粒体释放,并且在单独缺血10分钟和再灌注24小时后更为明显。缺血和再灌注对脑线粒体的这些作用可能会损害细胞内Ca 2+当重新充氧的线粒体暴露于异常高水平的细胞内Ca 2+时,体内稳态,降低有氧运动并增加无氧脑能量代谢,并增强细胞色素c依赖性的凋亡诱导。

更新日期:2017-10-16
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