The Role of the Mitochondrial UPR in Ischemic Protection

线粒体 UPR 在缺血保护中的作用

基本信息

批准号：
9223744
负责人：
Paul S Brookes
金额：
$ 61.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223744
关键词：
ATP-Binding Cassette Transporters Affect Animal Model Apoptotic Bioenergetics Biogenesis Biological Assay Bromides Caenorhabditis elegans Cardiac Cardiac Myocytes Cell Line Cell Nucleus Cell Survival Cells Chaperone Gene Complement Cytosol Data Disease Dominant-Negative Mutation Drug Metabolic Detoxication Electron Transport Employee Strikes Ethidium Generic Drugs Genes Genetic Genetic Models Glycolysis Heart Immunohistochemistry Injury Intervention Ion Transport Ischemia Laboratories Link Longevity Mammals Mediating Metabolic Metabolism Mitochondria Modeling Molecular Molecular Chaperones Monitor Mus Nuclear Organelles Orthologous Gene Oxygen Pathway interactions Peptide Hydrolases Peptides Pharmacology Physiological Play Predisposition Proteins RNA Interference Reagent Recovery Regulation Reperfusion Injury Reperfusion Therapy Research Resistance Resveratrol Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signaling Protein Sirtuins Specificity Stress System Techniques Testing Transgenes Transgenic Organisms Translating Up-Regulation Work biological adaptation to stress common cellular transcription factor ATF coronary artery occlusion gain of function in vivo inhibitor/antagonist insulin signaling mitochondrial dysfunction mutant novel prevent protein misfolding proteostasis proteotoxicity public health relevance response trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are central to ischemia-reperfusion (IR) injury and protection. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway that responds to mitochondrial dysfunction and proteotoxic stress. Our preliminary data suggests that the UPRmt protects against IR injury, consistent with up-regulation of mitochondrial chaperone genes, ROS detoxification machinery, and glycolytic capacity. In the genetic model organism C. elegans, the UPRmt's central mechanism of action has recently been described: mitochondrial proteotoxic stress regulates the matrix import and subsequent degradation of ATFS-1, a bZip transcription factor with dual targeting motifs. Under conditions of mild proteotoxic stress, matrix import is prevented through an ABC transport protein, HAF-1, acting in an undefined manner to suppress TIM/TOM activity. ATFS-1 instead traffics to the nucleus and activates a pro-survival repertoire of genes. Nuclear trafficking is both necessary and sufficient for protection, suggesting that the import of ATFS-1 into mitochondria provides a uniquely specific focal point for eliciting adaptation. This proposal aims to identify mechanisms through which the UPRmt protects C. elegans and to translate these findings to a mammalian cardiac model. Our approach will include defining mechanistic crosstalk with other signaling pathways that are also protective and will result in the identification of functional orthologs tha perform similarly in mammals as ATFS-1 and HAF-1.

描述（由申请人提供）：线粒体是缺血再灌注（IR）损伤和保护的核心。线粒体未折叠蛋白反应（UPRmt）是响应线粒体功能障碍和蛋白毒性应激的信号通路。我们的初步数据表明，UPRmt 具有保护作用。对抗 IR 损伤，与遗传模型生物 C 中线粒体伴侣基因、ROS 解毒机制和糖酵解能力的上调一致。在线虫中，UPRmt 的中心作用机制最近被描述为：线粒体蛋白毒性应激调节 ATFS-1 的基质输入和随后的降解，ATFS-1 是一种具有双重靶向基序的 bZip 转录因子。 ABC 转运蛋白 HAF-1 以一种不确定的方式抑制 TIM/TOM 活性，而是转运至细胞核并激活促生存的全部功能。核运输对于保护来说既是必要的也是充分的，这表明将 ATFS-1 导入线粒体为引发适应提供了一个独特的特定焦点。该提案旨在确定 UPRmt 保护线虫的机制并转化这些机制。我们的方法将包括定义与其他信号通路的机械串扰，这些信号通路也具有保护性，并将导致鉴定出在哺乳动物中与 ATFS-1 和 HAF-1 表现相似的功能直向同源物。