Mitochondrial-cytoskeletal interactions and aging

线粒体-细胞骨架相互作用与衰老

基本信息

批准号：
8664886
负责人：
Liza A Pon
金额：
$ 32.65万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664886
关键词：
Actins Aerobic Affect Age Aging Antioxidants Binding Cell Division Process Cell Polarity Cell division Cells Cytoskeleton Daughter Defect Disease Docking Endosomes Epithelial Event Exhibits F-Actin Functional disorder Generations Heterogeneity Human Immune Immune system Individual Inherited Intervention Link Longevity Mediating Mediator of activation protein Membrane Potentials Metabolic Control Metabolism Mitochondria Mitochondrial Inheritance Mothers Movement Muscle function Mutation Nervous system structure Neurodegenerative Disorders Neurons Oxidative Stress Parents Phenotype Population Premature aging syndrome Process Production Proteins Quality Control Reactive Oxygen Species Recombinant DNA Rejuvenation Role Saccharomycetales Site Skeletal Muscle Structure T-Cell Activation Testing Wound Healing Yeasts base catalase cell motility cell type daughter cell design experience fitness functional decline mutant oxidative damage polarized cell premature protein aggregate segregation senescence

项目摘要

DESCRIPTION (provided by applicant): Human babies are born young, independent of the age of their parents. Early studies revealed that daughter cells in yeast are also born young, with their full replicative lifespan, independent of the age of their mother cells. The identification of mother-daughter age asymmetry in budding yeast led to the hypothesis that aging determinants are asymmetrically distributed during yeast cell division. We obtained evidence that 1) there is heterogeneity in mitochondrial reactive oxygen species (ROS) within individual cells, 2) mitochondria with lower ROS, and are therefore fitter, are preferentially inherited by daughter cells, and 3) defects in mitochondrial quality control during inheritance perturbs mother-daughter age asymmetry. These studies indicate that mitochondria with low ROS are rejuvenation factors that contribute to daughter cell fitness and mother-daughter age asymmetry. We found that mitochondria that are destined for inheritance to daughter cells undergo actin-dependent movement from mother to daughter cells, and actin-dependent anchorage within the daughter cells. We also identified an actin-based mechanism for movement of cargos in the opposite direction, from buds to mother cells. We propose that these mechanisms contribute to mitochondrial quality control during inheritance, which in turn, contributes to mother-daughter age asymmetry. Interestingly, these same mechanisms have been implicated in segregation of mother-daughter age asymmetry determinants during yeast cell division, including clearance of oxidatively damaged protein aggregates from bud, and localization of the polarity factor, Bud6p in daughter cells. Equally important, we find that actin cables, the structures responsible for these segregation events, undergo an age-linked decline in organization and function. We propose that the decline in actin organization and function with age compromises segregation of age asymmetry determinants including high- and low-functioning mitochondria, which in turn, contributes to age-linked cellular dysfunction and loss of mother-daughter age asymmetry. Mitochondria have emerged as central regulators of lifespan, through their functions in aerobic energy mobilization, cellular metabolic control, and ROS production. The actin cytoskeleton has been implicated in enrichment of mitochondria at sites of polarized secretion in neurons, immune cells and yeast. In addition, age- associated declines in actin are linked to age-associated deficits in skeletal muscle function, epithelial wound healing, and T cell activation. We will study the mechanism underlying mitochondrial quality control during inheritance, and how this process changes with age. We will also determine how actin organization and function decline with age, and whether interventions that protect actin and mitochondrial quality control factors from declines with age can affect lifespan control. The proposed studies will extend our understanding of aging in yeast and other polarized cell types including neurons and immune cells that are targets for age-associated disease and senescence.

描述（由申请人提供）：人类婴儿是年轻的，独立于父母的年龄。早期研究表明，酵母中的子细胞也是年轻的，其全部复制寿命与母细胞的年龄无关。在萌芽酵母中鉴定母女年龄不对称性导致了以下假设：衰老决定因素在酵母细胞分裂过程中是不对称分布的。我们获得了证据，表明1）线粒体活性氧（ROS）在单个细胞内存在异质性，2）线粒体具有较低的ROS，因此具有贴合性，因此优先遗传了子细胞，而3）在遗传中，在遗传中，在遗传中，在遗传中，雌性女性伴随着女性的女性女性伴随着伴侣。这些研究表明，较低ROS的线粒体是恢复活力的因素，这些因素有助于女儿细胞健康和母女龄不对称。我们发现，注定要遗传给子女细胞的线粒体从母细胞到子细胞经历肌动蛋白依赖性运动，以及在子细胞内依赖肌动蛋白依赖的锚固。我们还确定了一种基于肌动蛋白的机制，用于从芽到母细胞的相反方向运动。我们建议这些机制在遗传过程中有助于线粒体质量控制，这反过来又导致了母女的年龄不对称性。有趣的是，这些相同的机制与酵母细胞分裂期间母女年龄不对称决定因素的分离有关，包括从芽中清除氧化损坏的蛋白质聚集体以及极性因子的定位，在子细胞中的芽6p。同样重要的是，我们发现肌动蛋白电缆，负责这些隔离事件的结构，组织和功能的年龄相关下降。我们建议，肌动蛋白组织的下降和随着年龄的功能损害了年龄不对称决定因素的分离，包括高功能和低功能的线粒体，这又导致了年龄连接的细胞功能障碍和母女年龄不对称的丧失。通过有氧能量动员，细胞代谢控制和ROS产生的功能，线粒体已成为寿命的中央调节剂。肌动蛋白细胞骨架与神经元，免疫细胞和酵母极化分泌部位的线粒体富集有关。此外，肌动蛋白的年龄相关下降与年龄相关的骨骼肌功能，上皮伤口愈合和T细胞激活有关。我们将研究继承期间线粒体质量控制的基础机制，以及该过程如何随着年龄的变化而变化。我们还将确定肌动蛋白的组织和功能如何随着年龄的增长而下降，以及保护肌动蛋白和线粒体质量控制因素免受年龄降低的干预措施是否会影响寿命控制。拟议的研究将扩展我们对酵母和其他极化细胞类型的衰老的理解，包括神经元和免疫细胞，这些神经元和免疫细胞是与年龄相关疾病和衰老的靶标。