Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling

定义内质网应激发育线粒体重塑

基本信息

批准号：
10537152
负责人：
Rockland Luke Wiseman
金额：
$ 235.62万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537152
关键词：
Acute Alzheimer&apos s Disease Apoptosis Apoptotic Biochemical Biological Biology Cardiolipins Cells Chronic Complex Crista ampullaris Cryo-electron tomography Development Disease Endoplasmic Reticulum Etiology Frontotemporal Dementia Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Inner mitochondrial membrane Lead Link Medical Genetics Membrane Mitochondria Molecular Morphology Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Outer Mitochondrial Membrane Oxidative Phosphorylation Pathogenesis Pathologic Phosphatidic Acid Phosphatidylethanolamine Phospholipids Progressive Supranuclear Palsy Proteins Regulation Respiration Signal Transduction Stress Tauopathies Testing Therapeutic Translations Work arm attenuation cytochrome c endoplasmic reticulum stress imaging approach insight metabolomics mitochondrial dysfunction mitochondrial membrane proteostasis response

项目摘要

PROJECT SUMMARY Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are intricately linked in the onset and pathogenesis of numerous neurodegenerative diseases such as Alzheimer’s disease (AD) and related tauopathies including progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). However, the pathologic relationship between ER stress and mitochondrial dysfunction in these diseases is currently poorly defined. Clinical, genetic, and biochemical evidence shows that imbalanced signaling through the PERK arm of the unfolded protein response (UPR) contributes to the neuronal dysfunction associated with many neurodegenerative diseases including those listed above. PERK integrates transcriptional and translational signaling to promote adaptive remodeling of mitochondrial proteostasis and function in response to acute ER stress. However, in response to chronic ER stress, PERK initiates apoptosis through complex mechanisms that involve mitochondrial dysfunction. This leads to the intriguing question: ‘How does PERK differentially regulate protective and pathologic aspects of mitochondrial function in response to varying levels of ER stress?’. We demonstrated that PERK-dependent translation attenuation promotes adaptive mitochondrial elongation in response to acute ER insults. Here, we will show that this change in mitochondrial morphology corresponds to PERK-dependent regulation of phospholipids within mitochondrial membranes. Intriguingly, changes in phospholipids are implicated in the pathogenesis of multiple neurodegenerative diseases. Further, mitochondrial phospholipids are key regulatory determinants for diverse aspects of mitochondrial biology including morphology, oxidative phosphorylation, and apoptosis. Here, we test the hypothesis that PERK-dependent regulation of mitochondrial phospholipids promotes adaptive remodeling of mitochondrial membranes during ER stress and that imbalances in this regulation contributes to the pathologic mitochondrial dysfunction observed during neurodegeneration. Using a combination of biochemical, metabolomic, and imaging-based approaches, we will define the molecular basis for PERK-dependent regulation of mitochondrial phospholipids and demonstrate the importance of this regulation in dictating mitochondrial morphology, cristae ultrastructure, and function in response to ER stress. Through these efforts, we will identify PERK-dependent regulation of mitochondrial phospholipids as a mechanism to adapt mitochondria in response to acute ER stress. Further, we will show that chronic PERK signaling induces pathologic alterations to mitochondrial phospholipids that contributes to the mitochondrial dysfunction associated with neurodegeneration. Collectively, our results will establish PERK-dependent remodeling of mitochondrial membrane phospholipids as a key determinant in dictating mitochondrial function in response to varying levels of ER stress. Further, our work will reveal new insights into the pathologic and therapeutic implications of PERK signaling on the mitochondrial dysfunction associated with the pathogenesis of neurodegenerative diseases including AD and related diseases.

项目概要内质网（ER）应激和线粒体功能障碍在发病和发生过程中有着复杂的联系。许多神经退行性疾病的发病机制，例如阿尔茨海默病（AD）和相关疾病 tau蛋白病包括进行性核上性麻痹（PSP）和额颞叶痴呆（FTD）。目前，这些疾病中 ER 应激与线粒体功能障碍之间的病理关系尚不明确临床、遗传和生化证据表明，PERK 臂的信号传导不平衡。未折叠蛋白反应 (UPR) 会导致与许多疾病相关的神经元功能障碍神经退行性疾病，包括上面列出的疾病，PERK 整合了转录和翻译。信号传导促进线粒体蛋白质稳态和功能的适应性重塑以响应急性 ER 然而，为了应对慢性 ER 应激，PERK 通过复杂的机制启动细胞凋亡。涉及线粒体功能障碍，这引出了一个有趣的问题：“PERK 是如何差异调节的” 线粒体功能响应不同水平的内质网应激的保护性和病理性方面？ PERK 依赖性翻译衰减被证明可促进适应性线粒体伸长在这里，我们将证明线粒体形态的这种变化对应于急性内质网损伤的反应。线粒体膜内磷脂的 PERK 依赖性调节。磷脂与多种神经退行性疾病的发病机制有关。磷脂是线粒体生物学各个方面的关键调节决定因素，包括形态、在此，我们检验了 PERK 依赖性调节的假设。线粒体磷脂促进 ER 期间线粒体膜的适应性重塑压力以及这种调节的不平衡会导致病理性线粒体功能障碍结合使用生化、代谢组学和成像技术进行观察。方法，我们将定义线粒体磷脂的 PERK 依赖性调节的分子基础并证明了这种调节在决定线粒体形态、嵴超微结构、通过这些努力，我们将确定 PERK 依赖性调节。线粒体磷脂作为一种使线粒体适应急性内质网应激的机制。将表明慢性 PERK 信号传导会诱导线粒体磷脂的病理改变总的来说，我们的结果将导致与神经变性相关的线粒体功能障碍。建立线粒体膜磷脂的 PERK 依赖性重塑作为关键决定因素此外，我们的工作将揭示新的线粒体功能以应对不同水平的内质网应激。深入了解 PERK 信号传导对线粒体功能障碍的病理和治疗影响与神经退行性疾病（包括 AD 和相关疾病）的发病机制有关。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.

DOI：
10.1038/s41467-023-39775-w
发表时间：
2023-07-11
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Rosarda, Jessica D.;Giles, Sarah;Harkins-Perry, Sarah;Mills, Elizabeth A.;Friedlander, Martin;Wiseman, R. Luke;Eade, Kevin T.
通讯作者：
Eade, Kevin T.