MITOCHONDRIAL FUNCTION IN ANESTHETIC PRECONDITIONING

本项目的总体目标是直接研究挥发性麻醉药的特殊作用 对线粒体功能的影响，导致麻醉诱导预处理（ARC）。我们特别假设 麻醉剂诱导线粒体生物能量学和离子通量的变化， 这种机制抑制或延迟线粒体通透性转换（PT）孔的开放， 在缺血和再灌注损伤期间。在目前的周期中，我们确定了肌膜KATP的作用， 通道作为抗氧化应激和细胞凋亡的保护剂。我们还获得了当地小说的证据 通过PKC、ROS和NO '调节线粒体KATP通道。我们发现分离的线粒体 在PCK依赖性细胞中，来自接受APC的心脏的细胞对Ca 2+诱导的PT孔开放更具抵抗力。 方式总之，这些数据有力地表明，线粒体功能的调节是核心， 短暂麻醉暴露后的心脏保护作用。 基于这些非常令人兴奋的结果和新的最先进的实验发展， 项目II将提供强有力的证据表明，抑制PT孔开放是一种最终的方法。 APC实际上影响心脏保护的机制。我们将致力于实现以下具体目标， 假设： 目标1.确定挥发性麻醉药对线粒体生物能量学、离子 稳态和蛋白质组。 目标二。描述麻醉剂如何调节PT孔开放。 目标3。确定sarcKATp通道对麻醉诱导的线粒体损伤的贡献 保护 目标4。应用计算模型定量和预测麻醉剂对线粒体的影响 生物能量学和功能。 综上所述，网络不仅是下游的目标，也是上游的发起者。 装甲运兵车这些研究将为研究APC信号通路的机制提供新的信息。 线粒体水平，这将导致新的治疗方法来治疗缺血再灌注损伤。 我们将研究全身麻醉剂如何保护心脏免受 缺血/再灌注损伤的线粒体和它们的胞质包膜之间的相互作用。这些结果 将为保护性治疗转化为临床实践提供有价值的信息。

The overall objective of this Project is to directly investigate the specific effects of volatile anesthetics on mitochondrial function that lead to anesthetic-induced preconditioning (ARC). We specifically hypothesize that anesthetics induce changes in mitochondrial bioenergetics and ion fluxes which through downstream mechanisms inhibit or delay opening of the mitochondrial permeability transition (PT) pore, a central event during ischemia and reperfusion injury. During the current cycle we identified a role for the sarcolemmal KATP channels as protectors against oxidative stress and apoptosis. We also obtained evidence on the novel local regulation of the mitochondrial KATP channel by PKC, ROS and NO'. We showed that mitochondria isolated from hearts subjected to APC were more resistant to Ca2+-induced PT pore opening in a PCK dependent manner. Together these data strongly suggest that regulation of mitochondria function is central for cardioprotection following transient anesthetic exposure. Based on these very exciting results and the development of novel state-of-the-art experimental approaches, Project II will furnish strong evidence that inhibition of PT pore opening is an ultimate mechanism by which APC actually affects cardioprotection. We will address the following Specific Aims and hypotheses: Aim 1. Determine the direct effects of volatile anesthetics on mitochondrial bioenergetics, ion homeostasis and proteome. Aim 2. Characterize how anesthetics modulate PT pore opening. Aim 3. Determine the contribution of sarcKATp channel to anesthetic-induced mitochondrial protection. Aim 4. Apply computational models to quantify and predict the effects of anesthetics on mitochondrial bioenergetics and function. In summary, the mitochondrion is not only a downstream target, but also an upstream initiator of APC. These studies will provide novel and mechanistic information of APC signaling pathways at the mitochondrial level which should lead to novel therapeutic approaches to treat ischemia reperfusion injury. Lay description: We will examine how general anesthetics protect the heart against ischemia/reperfusion injury by interactions between mitochondria and their cytosolic envelope. These results will furnish valuable information for translating protective therapies to clinical practice.