Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis

ATP合酶c亚基泄漏通道的结构和功能特征及其在AD发病机制中的作用

• 批准号: 10214094
• 负责人: Nelli Mnatsakanyan
• 金额: $ 15.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2022-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214094
• 关键词: Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Architecture; Binding; Biology; Brain; Calcium; Cell Death; Cell Death Induction; Cell Survival; Cells; Cleaved cell; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Detergents; Development; Energy Metabolism; Environment; Event; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Immobilization; In Situ; Individual; Inner mitochondrial membrane; Interferometry; Kinetics; Lipids; Liposomes; Literature; Measures; Membrane; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modeling; Molecular; Molecular Conformation; Mus; N-terminal; Neurodegenerative Disorders; Neurons; Oligomycins; Outer Mitochondrial Membrane; Pathogenesis; Pathologic; Pathway interactions; Permeability; Pharmacology; Play; Prevention strategy; Property; Proteins; Reporting; Research; Resolution; Role; Rupture; Signal Transduction; Structure; Synapses; System; Testing; Toxic effect; Transgenic Mice; cyclophilin D; cytochrome c; driving force; inhibitor/antagonist; mitochondrial dysfunction; mitochondrial membrane; mitochondrial permeability transition pore; monomer; mouse model; nanodisk; novel; novel therapeutics; overexpression; particle; patch clamp; prevent; reconstitution; sensor; time use

Abstract Mitochondrial and synaptic dysfunction are early pathological features and a driving force of Alzheimer's disease (AD) pathology. Aβ is found to accumulate abnormally in the brains of AD individuals and in an AD mouse models leading to mitochondrial Ca2+ overload and activation of mitochondrial permeability transition pore (mPTP). Prolonged opening of mPTP triggers outer mitochondrial membrane rupture, release of cytochrome c and activation of downstream cell death pathways. The mPTP has been at the center of extensive scientific research for the last several decades but it still remains as one of the most mysterious phenomena in biology today due to its controversial molecular composition and the lack of structural information of its pore. We have recently demonstrated the novel role of ATP synthase c-subunit ring in forming the channel of mPTP. Nevertheless, the gating mechanism of the ATP synthase c-subunit leak channel and conformational changes initiating its opening are yet to be discovered. In this proposal, we will use single-particle cryo-electron microscopy (cryo-EM) to identify the high- resolution structure and the open conformation of ATP synthase leak channel in the presence of channel modulators. We will also perform in situ structural analysis of ATP synthase in its functional environment within the Aβ-exposed primary hippocampal neurons and in mitochondria isolated from the mouse models of AD by using cryo-electron tomography (cryo-ET). In this project we will also investigate the direct role of ATP synthase leak channel as a novel cell death pathway in AD pathogenesis; we will test whether the pharmacological inhibition of this channel will rescue neurons from Aβ-induced cell death. Successful completion of this proposal will reveal the molecular mechanism(s) of mitochondrial permeability transition, the atomic structure of ATP synthase leak channel, and will aid in the development of new treatments for AD, targeting ATP synthase.

摘要