A 'Mitochondria-nucleus-ribosome' Signaling Axis Controls Lifespan in Mit Mutants
“线粒体-核-核糖体”信号轴控制线粒体突变体的寿命
基本信息
- 批准号:8840870
- 负责人:
- 金额:$ 17.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-05-01 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAgingAging-Related ProcessAlzheimer&aposs DiseaseAmericanAnabolismAnimalsBiochemical GeneticsCaenorhabditis elegansCell AgingCell NucleusCell divisionCellsChronicCockayne SyndromeComplexCongressesControl AnimalDNA DamageDNA Excision Repair Protein ERCC-6DNA Sequence AlterationDNA-Directed RNA PolymeraseDataDefectDegenerative DisorderDepressed moodDiploidyDiseaseElderlyElectron TransportEukaryotic CellFamilyFibroblastsFosteringFunctional disorderFutureGenesGenetic TranscriptionGoalsGrantHealthHeart DiseasesHousehold ConsumptionsHumanInvestigationLeadLifeLife ExtensionLightLinkLongevityMalignant NeoplasmsMeasuresMental DepressionMitochondriaMitochondrial ProteinsMusMutateMutationNational Research CouncilNematodaNon-Insulin-Dependent Diabetes MellitusNuclearNucleotidesOxidative PhosphorylationParkinson DiseasePatientsPersonal SatisfactionPhosphorylationPlayPopulationProcessProductionProteinsQuality of lifeRNA Polymerase IIRelative (related person)ReporterReverse Transcriptase Polymerase Chain ReactionRibonucleotidesRibosomesRoleSignal TransductionSiteSpecific qualifier valueTestingTimeTranscriptTranscription-Coupled RepairTransgenic OrganismsTranslatingTranslationsUracilWorkYeastsage relatedataxia telangiectasia mutated proteincell agefeedingflyimprovedinnovationmutantnovelnucleotide metabolismpolypeptidepreventprotein functionrepairedresponseretireetooltraffickingtranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of this study is to improve the health and well-being of older Americans. Our immediate goal is to examine how disruption of mitochondrial function is linked with the aging process. In recent years, it has become clear that defects in the electron transport chain of mitochondria, the key site of energy production in cells are linked with many age-related diseases - including heart disease, Type II diabetes, Parkinson Disease, Alzheimer's dementia, and cancer. 15% of the US population suffers from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems, it is clear that changes in mitochondria are involved, because their function is measurably altered. Perhaps most surprising has been the discovery of a number of mutants, across several species including mice, flies, nematodes and yeast, that paradoxically respond to mitochondrial electron transport chain dysfunction with increases in their lifespan. Investigation of this intriguing family of mutants is shedding new light on mitochondria and their role in aging.
In this study, we will examine aging in the Caenorhabditis elegans Mit mutants, which are all long-lived and contain defective mitochondrial electron transport chain activity. We have uncovered evidence for a novel, three component signaling cascade in these mutants that links disruption of mitochondrial ETC activity with nuclear checkpoint signaling, blockade of cytoplasmic ribosomal translation, and lifespan control. This is a completely unexpected finding because these processes span three distinct cellular compartments. Our current study will define the cause and effects of this novel signaling cascade. We hypothesize that disruption of nucleotide synthesis in Mit mutants underlies activation of their nuclear checkpoint response. We have identified three checkpoint proteins that are activated in these animals, and now our preliminary data points toward a direct ribosomal target that potentially acts as a key longevity control point by regulating trafficking of nuclear-encoded proteins to the mitochondria. Our specific objectives will be determined if the biosynthesis of ribonucleotides is altered in Mit mutants. We will also determine if there is nuclear transcriptional stalling in these animals. Finally we will test whether our identified ribosomal target does indeed differentially act to control translation of nuclear-encoded mitochondrial ETC transcripts following checkpoint activation. We will address these questions through the use of powerful biochemical and genetic tools. We will use LC-MS/MS to quantify changes in nucleotide pools, quantitative PCR to determine if transcriptional stalling is occurring, and a combination of transgenic reporters, polysomal profiling and RNA Seq to determine if nuclear-encoded mitochondrial proteins are differentially prevented from being translated in Mit mutants.
描述(由申请人提供):本研究的长期目标是改善美国老年人的健康和福祉。我们的近期目标是研究线粒体功能的破坏如何与衰老过程联系在一起。近年来,人们已经清楚地认识到,线粒体的电子传递链缺陷,细胞中能量产生的关键部位与许多与年龄有关的疾病有关-包括心脏病,II型糖尿病,帕金森病,阿尔茨海默氏痴呆症和癌症。15%的美国人口患有这些慢性退行性疾病。虽然还不能说线粒体导致了这些问题,但很明显线粒体的变化与此有关,因为它们的功能发生了可测量的改变。也许最令人惊讶的是在包括小鼠、苍蝇、线虫和酵母在内的几个物种中发现了许多突变体,这些突变体对线粒体电子传递链功能障碍的反应与其寿命的增加是矛盾的。对这个有趣的突变家族的研究为线粒体及其在衰老中的作用提供了新的线索。
在这项研究中,我们将研究秀丽隐杆线虫Mit突变体的衰老,这些突变体都是长寿的,并且含有缺陷的线粒体电子传递链活性。我们发现了这些突变体中新型三组分信号级联的证据,该级联将线粒体ETC活性的破坏与核检查点信号传导、细胞质核糖体翻译的阻断和寿命控制联系起来。这是一个完全出乎意料的发现,因为这些过程跨越三个不同的细胞区室。我们目前的研究将确定这种新型信号级联的原因和影响。我们推测,破坏核苷酸合成的Mit突变体的激活其核检查点反应的基础。我们已经确定了在这些动物中激活的三种检查点蛋白,现在我们的初步数据指向一个直接的核糖体靶点,该靶点可能通过调节核编码蛋白向线粒体的运输而作为关键的长寿控制点。如果核糖核苷酸的生物合成在Mit突变体中改变,我们的具体目标将被确定。我们还将确定这些动物中是否存在核转录停滞。最后,我们将测试我们确定的核糖体靶点是否确实在检查点激活后差异地控制核编码的线粒体ETC转录物的翻译。我们将通过使用强大的生化和遗传工具来解决这些问题。我们将使用LC-MS/MS来量化核苷酸库的变化,定量PCR来确定是否发生转录停滞,以及转基因报告基因,多聚体分析和RNA Seq的组合来确定核编码的线粒体蛋白是否被差异地阻止在Mit突变体中翻译。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The role of mitochondrial dysfunction in age-related diseases.
- DOI:10.1016/j.bbabio.2015.05.021
- 发表时间:2015-11
- 期刊:
- 影响因子:0
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SHANE L. REA其他文献
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{{ truncateString('SHANE L. REA', 18)}}的其他基金
A 'Mitochondria-nucleus-ribosome' Signaling Axis Controls Lifespan in Mit Mutants
“线粒体-核-核糖体”信号轴控制线粒体突变体的寿命
- 批准号:
8683435 - 财政年份:2014
- 资助金额:
$ 17.89万 - 项目类别:
Alternate Modes of Energy Production and clk-1 Life Extension
能量产生的替代模式和 clk-1 寿命延长
- 批准号:
7243998 - 财政年份:2006
- 资助金额:
$ 17.89万 - 项目类别:
Alternate Modes of Energy Production and clk-1 Life Extension
能量产生的替代模式和 clk-1 寿命延长
- 批准号:
7626207 - 财政年份:2006
- 资助金额:
$ 17.89万 - 项目类别:
Modes of Energy Production and clk-1 Life Extension
能量产生模式和 clk-1 寿命延长
- 批准号:
7040276 - 财政年份:2006
- 资助金额:
$ 17.89万 - 项目类别:
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