Molecular mechanisms of the mitochondrial permeability transition

我的研究计划的首要目标是识别和表征分子机制 负责应激诱导的线粒体内膜通透性。在大多数真核生物中 细胞，线粒体是它们以ATP形式提供的能量的主要来源，通过 进行氧化磷酸化(OXPHOS)。OXPHOS是一个分两步走的过程。第一，衬底 呼吸链的氧化导致线粒体产生电势 内膜。这种势能通过ADP的磷酸化来驱动ATP的产生 三磷酸腺苷合成酶复合体。防止能量耗散，确保OXPHOS是有效的线粒体 应严格控制内膜通透性，并将其维持在较低水平。应力条件 与钙和ROS动态平衡失调相关的可导致线粒体增加 内膜通透性--一种称为线粒体通透性转变(MPT)的现象。 MPT导致膜电位的耗散和线粒体ATP生成能力的丧失 导致细胞功能障碍和死亡。MPT与一系列疾病密切相关 从心脏病发作到神经退化。预防MPT对细胞死亡具有高度的保护作用 组织损伤表明有很高的治疗潜力。然而，MPT的分子机制并不是 众所周知，这一知识差距阻止了MPT成为药物靶点。在过去五年中 多年来，我们证明MPT是一种多方面的现象，取决于疾病的类型和 应激的严重性，它可以通过不同的途径发生。我们研究计划的中心目标是 确定MPT的特定分子机制与特定应激条件之间的联系。我们有 已经建立了几个与动物和细胞疾病相关的原始模型，导致不同类型的 MPT。在我们的方法中，测量MPT和组织损伤的各种方法， 细胞和线粒体水平与我们最初的电生理(贴片- 钳制)试验，允许在线粒体膜水平上直接测量MPT，并给出 美国有一个独特的机会来剖析和描述其多重身份和监管。结果是 我们的研究将提供对细胞死亡级联中最关键的事件之一的详细了解 并将为开发治疗方法带来必要的框架， 有选择地瞄准MPT。

The overarching goal of my research program is to identify and characterize molecular mechanisms responsible for stress-induced permeabilization of the mitochondrial inner membrane. In most eukaryotic cells, mitochondria are the primary source of the energy that they provide in the form of ATP by performing oxidative phosphorylation (OXPHOS). OXPHOS is a two-step process. First, substrate oxidation by the respiratory chain results in the generation of the electrical potential on the mitochondrial inner membrane. This potential energy drives generation of ATP by the phosphorylation of ADP at the ATP synthase complex. To prevent energy dissipation and ensure that OXPHOS is efficient mitochondrial inner membrane permeability should be tightly controlled and maintained at low levels. Stress conditions associated with dysregulation of calcium and ROS homeostasis can lead to an increase in mitochondrial inner membrane permeability – a phenomenon known as Mitochondrial Permeability Transition (mPT). mPT causes dissipation of the membrane potential and loss of mitochondrial ATP-generating capacity leading to cell dysfunction and death. mPT is critically involved in a broad spectrum of diseases ranging from heart attack to neurodegeneration. Prevention of mPT is highly protective against cell death and tissue damage suggesting high therapeutics potential. However, molecular mechanisms of mPT are not well understood, and this gap in knowledge prevents mPT from being a drug target. Over the past five years, we demonstrated that mPT is a multifaceted phenomenon and depending on the disease type and stress severity, it can occur through different pathways. The central goal of our research program is to identify the link between specific molecular mechanisms of mPT and specific stress conditions. We have already established several original animal and cell disease-relevant models causing different types of mPT. In our approach, a variety of methods that measure the mPT and tissue damage at the organismal, cellular and mitochondrial levels are coupled with a number of our original electrophysiological (patch- clamp) assays that allow direct measurement of mPT at the level of mitochondrial membranes and give us a unique opportunity to dissect and characterize its multiple identities and regulation. The results of our study will provide a detailed understanding of one of the most critical events in cell death cascades and will bring an essential framework for the development of therapeutically approaches that will selectively target mPT.