Molecular mechanisms of the mitochondrial permeability transition

线粒体通透性转变的分子机制

• 批准号: 10728363
• 负责人: Evgeny Pavlov
• 金额: $ 12.28万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728363
• 关键词: Animal Diseases; Biological Assay; Calcium; Cell Death; Cell Membrane Permeability; Cells; Cessation of life; Complex; Coupled; Disease; Drug Targeting; Electrophysiology (science); Energy-Generating Resources; Ensure; Eukaryotic Cell; Event; Functional disorder; Generations; Goals; Homeostasis; Inner mitochondrial membrane; Knowledge; Link; Measurement; Measures; Membrane Potentials; Methods; Mitochondria; Modeling; Molecular; Myocardial Infarction; Nerve Degeneration; Oxidative Phosphorylation; Pathologic; Pathway interactions; Permeability; Phosphorylation; Potential Energy; Prevention; Process; Regulation; Research; Respiratory Chain; Severities; Stress; Stroke; Therapeutic; Tissues; electrical potential; mitochondrial membrane; oxidation; patch clamp; prevent; programs; therapeutic development

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.

我的研究计划的首要目标是确定和表征分子机制 负责应激诱导的线粒体内膜透化。在大多数真核生物中， 线粒体是能量的主要来源，它们以ATP的形式提供能量， 进行氧化磷酸化（OXPHOS）。OXPHOS是一个两步过程。第一，基板 呼吸链的氧化导致在线粒体上产生电势 内膜这种势能通过ADP的磷酸化驱动ATP的产生， ATP合成酶复合物。为了防止能量耗散，并确保OXPHOS是高效的线粒体 应严格控制内膜渗透性并将其维持在低水平。应力条件 与钙和活性氧稳态失调相关的可能导致线粒体增加 内膜通透性-一种称为线粒体通透性转换（mPT）的现象。 mPT引起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与多种疾病密切相关， 从心脏病发作到神经退化预防mPT对细胞死亡具有高度保护作用， 组织损伤提示高治疗潜力。然而，mPT的分子机制不是 这种知识上的差距阻碍了mPT成为药物靶点。过去五 多年来，我们证明了mPT是一种多方面的现象，取决于疾病类型， 压力严重，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 已经建立了几种原始的动物和细胞疾病相关模型，导致不同类型的 mPT。在我们的方法中，各种测量mPT和组织损伤的方法， 细胞和线粒体水平与许多我们原始的电生理学（补丁， 钳）测定，其允许在线粒体膜水平直接测量mPT，并给出 我们有一个独特的机会，剖析和特点的多重身份和监管。的结果 我们的研究将提供细胞死亡级联中最关键事件之一的详细了解 并将为治疗方法的发展带来一个基本框架， 选择性靶向mPT。