Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases

线粒体通透性转换孔的分子组成及其在神经退行性疾病中的作用

• 批准号: 9905337
• 负责人: Nelli Mnatsakanyan
• 金额: $ 12.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905337
• 关键词: ATP Synthesis Pathway; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amino Acids; Amyloid beta-Protein; Attenuated; CRISPR/Cas technology; Calcium; Cell Death; Cell Death Induction; Cells; Cessation of life; Chronic; Complex; Coupling; Development; Devices; Disease; Energy Metabolism; Event; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Impairment; In Vitro; Individual; Inner mitochondrial membrane; Ion Channel; Lead; Measures; Membrane; Membrane Potentials; Mitochondria; Mitochondrial Swelling; Molecular; Molecular Conformation; Molecular Structure; Mus; Mutagenesis; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Outer Mitochondrial Membrane; Pathogenesis; Pathologic; Pathway interactions; Peptides; Peptidylprolyl Isomerase; Permeability; Pharmacology; Physiological; Play; Prevention strategy; Probability; Process; Production; Property; Publishing; Research; Role; Rupture; Stress; Structure; Synapses; System; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; age related neurodegeneration; arm; base; biophysical properties; cyclophilin D; design; driving force; excitotoxicity; genome editing; improved; mitochondrial membrane; mitochondrial permeability transition pore; mouse genome; mutant; neuron loss; neuronal survival; neurotoxicity; novel; novel therapeutics; overexpression; patch clamp; prevent; reconstitution; synaptic function; therapeutic target

Project Summary/Abstract Mitochondrial and synaptic dysfunction are early pathological features of Alzheimer's disease (AD) and other neurodegenerative diseases. The mitochondrial permeability transition pore (mPTP) is a mitochondrial ion channel that plays a central role in cell death during age- related neurodegeneration, therefore mPTP can serve as an important therapeutic target. Studies show that the major mPTP inducer, the peptidylprolyl isomerase cyclophilin D (CypD), interacts directly with the OSCP subunit of the stator arm of the mammalian ATP synthase. The stator arm stabilizes the connection between the ATP synthase catalytic (F1) and membrane (FO) portions. In AD, a complex of CypD and oligomeric Aβ peptide have been found to potentiate mPTP opening, resulting in impaired mitochondrial function, neuronal injury and death. We have recently suggested a novel role of the ATP synthase membrane embedded c- subunit in forming the pore of mPT. We have found further that the F1 portion of the ATP synthase gates the channel and that the loss of F1 components and OSCP during glutamate- induced excitotoxicity is correlated with neuronal death. We suggest that disruptions in interaction between the F1 and the stator arm during neuronal toxicity destabilize the ATP synthase structure, making the mitochondria more susceptible to mPT and cell death. In this proposal, using mutagenesis, we will investigate the molecular mechanisms that lead to the opening of the c-subunit leak channel, which converts the ATP synthase from an energy-conserving to an energy-dissipating, cell death-inducing, device. In order to attempt to enhance neuronal survival in the face of stress, we will perform mutations within the ATP synthase that modify the conformation of the ATP synthase, preventing mPT channel gating and decreasing channel conductance. Based on our mutagenesis findings we will design a transgenic mouse on the background of the AD model (Tg mAPP) mouse to study if neuroprotective ATP synthase mutations will protect the Tg mAPP mouse from the onset of AD- like features. We will also introduce the same mutations in non transgenic mouse to study the physiological roles of mPTP in the cell in general. Identifying molecular mechanisms underlying c-subunit gating will provide us with increased understanding of the role of mPTP in aging and neurodegeneration. The findings will lead to the design of specific and potent therapeutic compounds to target the mPTP directly, resulting in preventative strategies for neurodegenerative disease.

项目总结/摘要 线粒体和突触功能障碍是阿尔茨海默病的早期病理特征 疾病（AD）和其他神经退行性疾病。线粒体通透性转换 孔（mPTP）是一种线粒体离子通道，在衰老期间的细胞死亡中发挥核心作用- 因此，mPTP可以作为重要的治疗靶点。 研究表明，主要的mPTP诱导剂，肽基脯氨酰异构酶亲环素D（CypD）， 直接与哺乳动物ATP合酶定子臂的OSCP亚基相互作用。的 定子臂稳定ATP合酶催化（F1）和膜之间的连接 (FO)部分。在AD中，发现CypD和寡聚Aβ肽的复合物 增强mPTP开放，导致线粒体功能受损、神经元损伤和 死亡 我们最近提出了一个新的作用的ATP合酶膜嵌入c- 亚基形成mPT的孔。我们进一步发现ATP的F1部分 合成酶门控通道，并且在谷氨酸- 诱导的兴奋性毒性与神经元死亡相关。我们建议， 在神经元毒性期间，F1和定子臂之间的相互作用使ATP不稳定 合成酶结构，使线粒体更容易受到mPT和细胞死亡。 在这个提议中，我们将使用诱变，研究分子机制， 导致c亚基泄漏通道的开放，其将ATP合酶从 节能到一个能量耗散，细胞死亡诱导，设备。以便尝试 增强神经元在压力面前的存活，我们将在ATP内进行突变， ATP合酶，其改变ATP合酶的构象，阻止mPT通道门控， 降低沟道电导。基于我们的诱变发现，我们将设计一个 在AD模型（Tg mAPP）小鼠的背景上的转基因小鼠，以研究是否 神经保护性ATP合酶突变将保护Tg mAPP小鼠免于AD的发作。 相似的特征。我们还将在非转基因小鼠中引入相同的突变，以研究 一般来说，mPTP在细胞中的生理作用。 确定c亚基门控的分子机制将为我们提供 增加对mPTP在衰老和神经退行性变中作用的理解。其成果将 导致设计特异性和有效的治疗化合物以直接靶向mPTP， 从而导致神经变性疾病的预防策略。