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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

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.

摘要线粒体功能缺陷导致细胞在应激条件下损伤和死亡。在Organismal 线粒体水平功能障碍发生在由基因突变引起的线粒体疾病中，神经退行性变，并且在衰老期间严重程度较低，损害脆弱组织，如大脑和骨骼肌肉.线粒体突变导致破坏能量代谢的失败，包括还原/氧化失衡和炎症导致组织损伤并最终死亡。线粒体缺陷细胞依赖糖酵解产生能量，与线粒体疾病患者相似，压力条件。导致这种细胞损伤的机制以及线粒体缺陷细胞如何被保护免受损害和死亡的情况在很大程度上是未知的。这很重要，因为没有治愈方法线粒体疾病和功能障碍的线粒体是衰老或神经变性的标志之一。在遗传和化学高通量筛选中，我们的实验室已经确定了抗生素的一个子集，包括四环素类，靶向线粒体蛋白翻译，并在细胞内拯救细胞死亡和炎症和线粒体疾病的小鼠模型。四环素促进的细胞存活依赖于抑制内质网应激和未折叠蛋白反应（UPR）是独立的转录因子ATF 4。的四环素诱导的有丝分裂体停滞/分裂如何保护细胞免受细胞死亡，线粒体疾病的小鼠临床前模型是未知的。我们假设一种信号机制在线粒体缺陷细胞的情况下，在停滞/分裂的线粒体体处起始的蛋白质促进细胞存活，人类疾病突变。这个应用程序的主要目标是识别信号和细胞由停滞和分裂的线粒体引起的机制，促进细胞存活并决定细胞的增殖。在线粒体疾病的细胞和小鼠模型中的功效。我们建议：（1）确定初始部分停滞/分裂线粒体的信号传导机制促进线粒体疾病的存活突变细胞，重点是MALSU分裂因子和其他与线粒体相关的蛋白质; 2）分析停滞/分裂的线粒体的下游组分，其促进线粒体中的存活，疾病突变细胞，重点是将停滞/分裂的线粒体与ER应激IRE 1a联系起来的组分， UPR反应和3）分析四环素类似物在Ndufs 4 KO小鼠（线粒体复合物）中的作用 I缺陷小鼠模型，重点是四环素类药物对健康，存活和线粒体调节的影响在Ndufs 4 KO小鼠中的信号传导/ER应激和脑和骨骼肌免疫炎症的抑制。的本申请的结果将决定由基因启动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/分裂的线粒体。这些机制将促进我们对保护细胞的线粒体蛋白质翻译和信号机制的理解在线粒体失调和疾病的背景下的损害。