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

项目概要/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。线粒体通透性转变 pore (mPTP) 是一种线粒体离子通道，在衰老过程中的细胞死亡中发挥着核心作用。 相关的神经退行性变，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蛋白 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，CypD 和寡聚 Aβ 肽的复合物被发现可以 增强 mPTP 开放，导致线粒体功能受损、神经元损伤和 死亡。 我们最近提出了嵌入 c- 的 ATP 合成酶膜的新作用 形成 mPT 孔的亚基。我们进一步发现 ATP 的 F1 部分 合酶门控通道，并且在谷氨酸-过程中 F1 成分和 OSCP 的损失 诱导的兴奋性毒性与神经元死亡相关。我们建议，中断 神经元毒性期间 F1 和定子臂之间的相互作用使 ATP 不稳定 合酶结构，使线粒体更容易受到 mPT 和细胞死亡的影响。 在这个提案中，我们将利用诱变研究分子机制 导致 c 亚基泄漏通道的打开，将 ATP 合酶从 能量守恒到能量耗散、诱导细胞死亡的设备。为了尝试 增强神经元在面对压力时的存活率，我们将在 ATP 内进行突变 修饰 ATP 合酶构象的合成酶，防止 mPT 通道门控和 降低通道电导。根据我们的诱变发现，我们将设计一个 以 AD 模型 (Tg mAPP) 小鼠为背景的转基因小鼠研究是否 神经保护性 ATP 合酶突变将保护 Tg mAPP 小鼠免受 AD- 喜欢特征。我们还将在非转基因小鼠中引入相同的突变来研究 mPTP 在细胞中的一般生理作用。 识别 c 亚基门控的分子机制将为我们提供 增加了对 mPTP 在衰老和神经退行性疾病中的作用的了解。研究结果将 导致设计出直接靶向 mPTP 的特异性和有效的治疗化合物， 从而制定神经退行性疾病的预防策略。

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.