权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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