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：
9357484
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/9357484
关键词：
Affect Age Age-Years Aging Aging-Related Process 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 Proliferating Proteins Pseudomonas aeruginosa Recovery Repression Respiratory Chain Role Signal Transduction Starvation Testing Time Toxic effect Toxin Virus Work 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.

项目概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。线粒体衰退的一个潜在原因是有害线粒体的繁殖正如在个体肌肉中观察到的那样，生物体整个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合酶成分和损伤导致氧化磷酸化 (OxPhos) 缺乏。因为每个细胞中 mtDNA 存在 100-1000 个拷贝，单个基因组中的损伤具有良好的耐受性。然而，如果有害基因组积累超过~60%，与相关的病理学 OxPhos 功能障碍随之而来，包括细胞变性和死亡。目前尚不清楚如何有害线粒体DNA的存在、它们如何繁殖以及最终为何有毒。细胞响应 OxPhos 缺乏的一种机制是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。我们发现 UPRmt 激活可针对以下原因引起的 OxPhos 缺陷提供保护： OxPhos 基因或针对细菌衍生毒素的核突变（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 需要在异质性秀丽隐杆线虫模型中维持和传播有害的线粒体DNA。因此，我们假设有害的 mtDNA 是自私的或寄生的，并利用内源性应激反应程序可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 的后果传播是与年龄相关的线粒体功能障碍的一个促成因素。