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.

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.

项目成果

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

不平衡展开的蛋白质反应信号传导有助于1-脱氧胆脂性视网膜毒性。

• 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.