MAINTENANCE OF MITOCHONDRIAL PROTEIN FOLDING AS AN AGING EFFECTOR

线粒体蛋白折叠作为衰老效应物的维持

基本信息

批准号：
9923550
负责人：
Cole M Haynes
金额：
$ 34.34万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923550
关键词：
Affect Age Age-Years Aging Biopsy Buffers Caenorhabditis elegans Cell Nucleus Cell physiology Cells Cessation of life Clinical Cyanides Data Defect Development Developmental Delay Disorders Disease Environment Exposure to FRAP1 gene Functional disorder Generations Genes Genetic Transcription Genome Goals Growth Impairment Individual Inner mitochondrial membrane Lesion Life Experience Longevity Maintenance Mediating Metabolism Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Molecular Chaperones Muscle Muscle Cells Mutation Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Organelles Organism Oxidative Phosphorylation Oxidative Phosphorylation Deficiency Parkinson Disease Pathology Pathway interactions Patients Post-Translational Protein Processing Process Proliferating Proteins Pseudomonas aeruginosa Recovery Repression Respiratory Chain Role Signal Transduction Starvation Testing Time Toxic effect Toxin Virus Work activating transcription factor 1 biological adaptation to stress common cellular transcription factor ATF design dopaminergic neuron experimental study improved mitochondrial dysfunction mitochondrial genome neuronal cell body normal aging nutrition pathogen prevent programs protein folding repaired response

项目摘要

Project Summary Mitochondrial function declines with age and is exacerbated in disease states such as Parkinson's. One potential cause of the mitochondrial decline is the propagation of deleterious mitochondrial genomes (mtDNAs) throughout an organism's lifetime as has been observed in individual muscle cells or dopaminergic neurons. mtDNAs only encode respiratory chain and ATP synthase components and thus lesions result in oxidative phosphorylation (OxPhos) deficiency. Because mtDNAs exist at 100s-1000s of copies per cell, a lesion in a single genome is well tolerated. However, if the deleterious genome accumulates to greater than ~60%, pathology related to OxPhos dysfunction ensues including cell degeneration and death. It is currently unclear how deleterious mtDNAs are maintained, how they are propagated and ultimately why they are toxic. One mechanism by which cells respond to OxPhos deficiency is by activating the mitochondrial unfolded protein response (UPRmt), which initiates a mitochondrial repair and recovery program. We have found that UPRmt activation provides protection against OxPhos deficiencies caused by nuclear mutations in OxPhos genes or against bacterial derived toxins (P. aeruginosa produces cyanide for example). Our surprising preliminary data indicate that the UPRmt is required to maintain and propagate deleterious mtDNAs in a C. elegans model of heteroplasmy. Therefore, we hypothesize that deleterious mtDNAs are selfish, or parasitic, and take advantage of an endogenous stress response program in place to repair and respond to mitochondrial dysfunction. Here, we plan to examine the consequences of UPRmt activation and deleterious mtDNA propagation as a contributor to age-associated mitochondrial dysfunction.

项目摘要线粒体功能随着年龄的增长而下降，并且在帕金森病等疾病状态下会加剧。线粒体下降的潜在原因之一是有害线粒体的传播在单个肌肉中观察到的整个生物体生命周期中的基因组（mTDNA）细胞或多巴胺能神经元。 MTDNA仅编码呼吸链和ATP合酶成分及其病变导致氧化磷酸化（OXPHOS）缺乏。因为 MTDNA存在于每个细胞的100s-1000拷贝，单个基因组中的病变耐受性良好。但是，如果有害基因组累积到大于约60％，则与随之而来的是包括细胞变性和死亡，包括Oxphos功能障碍。目前尚不清楚如何维持有害的mtdnas，如何传播它们，最终它们是有毒的原因。细胞对Oxphos缺乏反应的一种机制是激活线粒体展开的蛋白质反应（UPRMT），启动了线粒体修复和恢复程序。我们发现UPRMT激活提供了针对由Oxphos缺陷的保护 Oxphos基因或针对细菌衍生毒素的核突变（铜绿假单胞菌会产生例如）。我们令人惊讶的初步数据表明，UPRMT需要在异质的秀丽隐杆线虫模型中维持并传播有害的mtdnas。因此，我们假设有害的mtdnas是自私的或寄生的，并利用了一个内源性应力反应计划适当地修复和应对线粒体功能障碍。在这里，我们计划检查UPRMT激活和有害mtDNA的后果传播是导致年龄相关的线粒体功能障碍的贡献者。