Schizophrenia etiology is unknown, nevertheless imbalances occurring in an acute psychotic episode are important to its development, such as alterations in cellular energetic state, REDOX homeostasis and intracellular Ca2+ management, all of which are controlled primarily by mitochondria. However, mitochondrial function was always evaluated singularly, in the presence of specific respiratory substrates, without considering the plurality of the electron transport system. In this study, mitochondrial function was analyzed under conditions of isolated or multiple respiratory substrates using brain mitochondria isolated from MK-801-exposed mice. Results showed a high H2O2 production in the presence of pyruvate/malate, with no change in oxygen consumption. In the condition of multiple substrates, however, this effect is lost. The analysis of Ca2+ retention capacity revealed a significant change in the uptake kinetics of this ion by mitochondria in MK-801-exposed animals. Futhermore, when mitochondria were exposed to calcium, a total loss of oxidative phosphorylation and an impressive increase in H2O2 production were observed in the condition of multiple substrates. There was no alteration in the activity of the antioxidant enzymes analyzed. The data demonstrate for the first time, in an animal model of psychosis, two important aspects (1) mitochondria may compensate deficiencies in a single mitochondrial complex when they oxidize several substrates simultaneously, (2) Ca2+ handling is compromised in MK-801-exposed mice, resulting in a loss of phosphorylative capacity and an increase in H2O2 production. These data favor the hypothesis that disruption of key physiological roles of mitochondria may be a trigger in acute psychosis and, consequently, schizophrenia.

中文翻译：

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在与急性精神病相关的模型中，多种底物的增能和钙激发揭示了脑线粒体功能障碍。

精神分裂症的病因尚不清楚，但是在急性精神病发作中发生的失衡对其发展很重要，例如细胞能量状态的改变，氧化还原稳态和细胞内Ca2 +管理，所有这些主要由线粒体控制。但是，线粒体功能始终在存在特定呼吸底物的情况下单独进行评估，而无需考虑多个电子传输系统。在这项研究中，使用分离自MK-801暴露小鼠的脑线粒体，在分离的或多种呼吸底物的条件下分析了线粒体功能。结果表明，在丙酮酸/苹果酸的存在下，H2O2的产量很高，而氧气消耗没有变化。但是，在多个基板的情况下，这种效果消失了。Ca 2+保留能力的分析显示，在暴露于MK-801的动物中，线粒体对该离子的吸收动力学有显着变化。此外，当线粒体暴露于钙时，在多种底物的条件下，氧化磷酸化的总损失和H2O2产量的显着增加被观察到。分析的抗氧化酶的活性没有变化。数据首次证明，在精神病动物模型中，两个重要方面（1）当线粒体同时氧化多种底物时，线粒体可以弥补单个线粒体复合体的缺陷；（2）在暴露于MK-801的情况下，Ca2 +处理受到损害小鼠，导致磷酸化能力的丧失和H2O2产量的增加。