Mitoribosome protein translation signaling and survival mechanisms

线粒体核糖体蛋白翻译信号传导和生存机制

基本信息

批准号：
10714636
负责人：
Pere Puigserver
金额：
$ 72.73万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714636
关键词：
Address Affect Age Aging Antibiotics Applications Grants Bioenergetics Brain Cell Death Cell Survival Cell model Cells Cessation of life Chemicals Cytoprotection Cytosol DNA Sequence Alteration Defect Disease Doxycycline Electron Transport Endoplasmic Reticulum Degradation Pathway Energy Metabolism Exhibits Failure Functional disorder Generations Genetic Glycolysis Goals Heat shock proteins Heterogeneity Homeostasis Human Hypoxia Immune Inflammation Inflammatory Intervention Knockout Mice Laboratories Leigh Disease Link MAP Kinase Gene Measures Mediating Messenger RNA Mitochondria Mitochondrial Diseases Mitochondrial Proteins Mitochondrial complex I deficiency Molecular Mus Mutation Nature Nerve Degeneration Nutrient Outcome Outcome Study Oxidation-Reduction Oxidative Phosphorylation Pathogenicity Patients Phenotype Pre-Clinical Model Protein Kinase Proteins Proteomics Ribosomes Series Severities Signal Transduction Skeletal Muscle Stress Tetracyclines Tissues Transcript Translational Repression Translations analog biological adaptation to stress cell injury efficacy evaluation endoplasmic reticulum stress expectation fitness high throughput screening human disease improved link protein mTOR inhibition mitochondrial dysfunction mouse model mutant p38 Mitogen Activated Protein Kinase protective efficacy response transcription factor

Address Affect Age Aging Antibiotics Applications Grants Bioenergetics Brain Cell Death Cell Survival Cell model Cells Cessation of life Chemicals Cytoprotection Cytosol DNA Sequence Alteration Defect Disease Doxycycline Electron Transport Endoplasmic Reticulum Degradation Pathway Energy Metabolism Exhibits Failure Functional disorder Generations Genetic Glycolysis Goals Heat shock proteins Heterogeneity Homeostasis Human Hypoxia Immune Inflammation Inflammatory Intervention Knockout Mice Laboratories Leigh Disease Link MAP Kinase Gene Measures Mediating Messenger RNA Mitochondria Mitochondrial Diseases Mitochondrial Proteins Mitochondrial complex I deficiency Molecular Mus Mutation Nature Nerve Degeneration Nutrient Outcome Outcome Study Oxidation-Reduction Oxidative Phosphorylation Pathogenicity Patients Phenotype Pre-Clinical Model Protein Kinase Proteins Proteomics Ribosomes Series Severities Signal Transduction Skeletal Muscle Stress Tetracyclines Tissues Transcript Translational Repression Translations analog biological adaptation to stress cell injury efficacy evaluation endoplasmic reticulum stress expectation fitness high throughput screening human disease improved link protein mTOR inhibition mitochondrial dysfunction mouse model mutant p38 Mitogen Activated Protein Kinase protective efficacy response transcription factor

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项目摘要

Abstract Defective mitochondrial function causes cellular damage and death under stress conditions. At the organismal level mitochondrial dysfunction occurs in mitochondrial diseases caused by genetic mutations, neurodegeneration, and with less severity during aging, damaging vulnerable tissues such as brain and skeletal muscle. Mitochondrial mutations cause failures that disrupt energy metabolism, including reductive/oxidative imbalances and inflammation that lead to tissue damage and eventually death. Mitochondrial defective cells depend on glycolysis for energy generation and, similar to mitochondrial disease patients, are vulnerable to stress conditions. The mechanisms that cause this cell damage and how mitochondrial defective cells can be protected against damage and death are largely unknown. This is important because there are no cures for mitochondrial diseases, and dysfunctional mitochondria is one of the hallmarks of aging or neurodegeneration. In genetic and chemical high throughput screens our laboratory has identified a subset of antibiotics, including tetracyclines, that target the mitoribosome protein translation, and rescue cell death and inflammation in cellular and mouse models of mitochondrial diseases. Tetracyclines-promoted cell survival depends on suppression of ER stress and Unfolded Protein Response (UPR) that is independent of the transcription factor ATF4. The mechanisms of how tetracycline-induced mitoribosome stalling/splitting protect against cell death in cellular and mouse pre-clinical models of mitochondrial diseases is unknown. We hypothesize that a signaling mechanism initiated at the stalled/split mitoribosome promotes cell survival in the context of mitochondrial defective cells and human disease mutations. The main goal of this application is to identify the signaling and cellular mechanisms caused by stalled and split mitoribosomes that promote cell survival and determine the efficacy in cellular and mouse models of mitochondrial diseases. We propose 1) to determine the initial signaling mechanism at the partial stalled/split mitoribosome that promotes survival in mitochondrial disease mutant cells, focusing on MALSU splitting factor and additional proteins associated at the mitoribosome; 2) to analyze the components downstream of the stalled/split mitoribosome that promote survival in mitochondrial disease mutant cells, focusing on components that link the stalled/split mitoribosome to ER stress IRE1a and UPR responses and 3) to analyze the effects of tetracycline analogs in Ndufs4 KO mice, a mitochondrial complex I deficient mouse model, focusing on the effects tetracyclines on fitness, survival and modulation of mitoribosome signaling/ER stress and suppression of brain and skeletal muscle immune inflammation in Ndufs4 KO mice. The outcomes of this application will determine the regulatory and signaling mechanisms that are initiated by the stalled/split mitoribosome in conditions of defective mitochondrial disease mutations. These mechanisms will advance our understanding of mitoribosome protein translation and signaling mechanisms that protect cell damage in the context of mitochondrial dysregulation and diseases.

抽象的线粒体功能有缺陷会在应力条件下导致细胞损伤和死亡。在生物体线粒体功能障碍在基因突变引起的线粒体疾病中发生神经变性，在衰老期间严重程度较小，破坏脆弱组织（例如大脑和骨骼）肌肉。线粒体突变会导致破坏能量代谢的失败，包括还原/氧化失衡和炎症会导致组织损伤并最终死亡。线粒体有缺陷的细胞取决于能量产生的糖酵解，类似于线粒体疾病患者，很容易受到影响压力条件。导致该细胞损伤的机制以及线粒体有缺陷的细胞如何是免受损害和死亡的保护在很大程度上是未知的。这很重要，因为没有治疗方法线粒体疾病和功能失调的线粒体是衰老或神经变性的标志之一。在遗传和化学高吞吐量中，我们的实验室已经确定了一部分抗生素，包括四环素，靶向身体体蛋白翻译，并挽救细胞死亡和细胞炎症和线粒体疾病的小鼠模型。四环素促进的细胞存活取决于抑制与转录因子ATF4无关的ER应力和展开的蛋白质反应（UPR）。这四环素诱导的地球体降低/分裂如何防止细胞中的细胞死亡的机制小鼠线粒体疾病的临床前模型尚不清楚。我们假设一种信号传导机制在停滞/裂开的形态体中启动可在线粒体有缺陷的细胞和人类疾病突变。该应用程序的主要目标是识别信号和细胞由失速和分裂的形状体引起的机制，可促进细胞存活并确定线粒体疾病的细胞和小鼠模型的功效。我们建议1）确定初始促进线粒体疾病生存的部分失速/分裂形态体的信号传导机制突变细胞，专注于Malsu分裂因子和在平线体处相关的其他蛋白质； 2）到分析促进线粒体生存的停滞/分裂形状体下游的成分疾病突变细胞，专注于将失速/裂开的形状体连接到ER胁迫IRE1A和 UPR响应和3）分析四环素类似物在线粒体复合物NDUFS4 KO小鼠中的影响我缺乏小鼠模型，重点介绍了四环素对适应性，生存和调节的效果 NDUFS4 KO小鼠的信号传导/ER应力以及脑和骨骼肌免疫炎症的抑制。这该应用的结果将确定由该应用的调节和信号传导机制在有缺陷的线粒体疾病突变的条件下，停滞/分裂的身体体。这些机制会促进我们对保护细胞的Mitoribosomy蛋白翻译和信号传导机制的理解线粒体失调和疾病的损害。