Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling

定义内质网应激发育线粒体重塑

• 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
• 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' 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

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.

项目摘要 内质网（ER）应力和线粒体功能障碍在发作和 许多神经退行性疾病（例如阿尔茨海默氏病）（AD）和相关的发病机理 包括渐进性超纤毛麻痹（PSP）和额颞痴呆（FTD）的auopathies。但是， 目前，ER应力与线粒体功能障碍之间的病理关系目前很差 定义。临床，遗传和生化证据表明，通过 展开的蛋白质反应（UPR）有助于与许多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综合转录和翻译 信号传导以促进线粒体蛋白抑制剂的适应性重塑和响应急性ER的功能 压力。但是，在响应慢性ER应力时，PERK通过复杂机制引发凋亡， 涉及线粒体功能障碍。这导致了一个有趣的问题：‘振兴如何差异化调节 线粒体功能的保护性和病理方面响应不同水平的ER压力吗？’。我们 证明PERK依赖性翻译衰减促进了适应性线粒体伸长 对急性ER侮辱的反应。在这里，我们将证明线粒体形态的这种变化与 线粒体膜中磷脂的PERK依赖性调节。有趣的是，变化 多种神经退行性疾病的发病机理暗示磷脂。此外，线粒体 磷脂是线粒体生物学潜水方面的关键调节性决定者，包括形态学， 氧化磷酸化和凋亡。在这里，我们检验了以下假设 线粒体磷脂促进ER期间线粒体膜的适应性重塑 压力和该调节中的失衡有助于病理线粒体功能障碍 在神经退行性期间观察到。结合生化，代谢组和基于成像的组合 方法是，我们将定义依赖于线粒体磷脂的PERK依赖性调节的分子基础 并证明了该法规在决定线粒体形态，cristae超微结构中的重要性， 并响应质网应力而起作用。通过这些努力，我们将确定对 线粒体磷脂作为响应急性ER应激的线粒体适应线粒体的机制。此外，我们 将表明，慢性PERK信号传导会引起对线粒体磷脂的病理改变，即 有助于与神经变性相关的线粒体功能障碍。总的来说，我们的结果将 建立对线粒体膜磷脂的PERK依赖性重塑作为关键确定剂 响应不同水平的ER应力来决定线粒体功能。此外，我们的工作将揭示新的 对PERK信号对线粒体功能障碍的病理和治疗意义的见解 与包括AD和相关疾病在内的神经退行性疾病的发病机理有关。

项目成果

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.