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

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，并在帕金森氏症等疾病状态下加剧。线粒体减少的一个潜在原因是有害的线粒体增殖，正如在个体肌肉中观察到的那样，细胞或多巴胺能神经元。线粒体DNA只编码呼吸链和ATP合酶因此，损伤导致氧化磷酸化（OxPhos）缺乏。因为 mtDNA在每个细胞中以100 - 1000个拷贝存在，单个基因组中的损伤是良好耐受的。然而，如果有害基因组累积到大于~ 60%，则与 OxPhos功能障碍包括细胞变性和死亡。目前尚不清楚如何有害的mtDNA是如何维持的，它们是如何繁殖的，以及最终为什么它们是有毒的。细胞响应OxPhos缺乏的一种机制是通过激活线粒体未折叠蛋白反应（UPRmt），启动线粒体修复和恢复程序。我们已经发现，UPRmt活化提供了针对由以下引起的OxPhos缺陷的保护： OxPhos基因的核突变或针对细菌衍生的毒素（铜绿假单胞菌产生例如氰化物）。我们令人惊讶的初步数据表明，UPRmt需要维持和传播有害的mtDNA。elegans异质性模型。所以我们假设有害mtDNA是自私的或寄生的，内源性应激反应程序到位，以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，繁殖作为一个贡献者年龄相关的线粒体功能障碍。