Mitochondrial-cytoskeletal interactions and aging

线粒体-细胞骨架相互作用与衰老

• 批准号: 8050332
• 负责人: Liza A Pon
• 金额: $ 32.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8050332
• 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

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. PUBLIC HEALTH RELEVANCE: Mitochondria have emerged as central regulators of aging through their function in energy production, central metabolism and oxidative stress. We find that fitter mitochondria, which have lower oxidative damage, are selectively transferred from mother cells to daughter cells during yeast cell division, and that this process contributes to the fitness and full lifespan of new daughter cells. We have identified mechanisms for inheritance of the fittest mitochondria that are conserved in cells of the nervous and immune systems. Finally, we find that this process is compromised with age and may contribute to age-linked neurodegenerative diseases and immune senescence. We will study the mechanisms for segregation of mitochondria and other aging determinants, and for age-linked declines in these processes.

描述（由申请人提供）：人类婴儿出生时很年轻，与父母的年龄无关。早期的研究表明，酵母中的子细胞出生时也很年轻，具有完整的复制寿命，与母细胞的年龄无关。出芽酵母中母女年龄不对称的鉴定导致了衰老决定因素在酵母细胞分裂过程中不对称分布的假设。我们获得的证据表明：1)单个细胞内线粒体活性氧（ROS）存在异质性；2)活性氧较低的线粒体更适合被子细胞优先遗传；3)遗传过程中线粒体质量控制缺陷扰乱了母女年龄不对称。这些研究表明，具有低ROS的线粒体是促进子细胞健康和母女年龄不对称的年轻化因素。我们发现，注定遗传给子细胞的线粒体经历了动作蛋白依赖的运动，从母细胞到子细胞，以及在子细胞内的动作蛋白依赖的锚定。我们还发现了一种基于肌动蛋白的机制，用于从芽到母细胞的反方向运动。我们认为这些机制有助于遗传过程中的线粒体质量控制，从而导致母女年龄不对称。有趣的是，这些相同的机制与酵母细胞分裂过程中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伤的蛋白质聚集体，以及极性因子Bud6p在子细胞中的定位。同样重要的是，我们发现肌动蛋白索，负责这些分离事件的结构，经历了与年龄相关的组织和功能下降。我们提出，肌动蛋白组织和功能随年龄的下降损害了年龄不对称决定因素的分离，包括高功能和低功能线粒体，这反过来又导致了年龄相关的细胞功能障碍和母女年龄不对称的丧失。线粒体通过其有氧能量动员、细胞代谢控制和ROS产生的功能，已成为寿命的中心调节器。肌动蛋白细胞骨架与线粒体在神经元、免疫细胞和酵母的极化分泌位点的富集有关。此外，与年龄相关的肌动蛋白下降与骨骼肌功能、上皮伤口愈合和T细胞活化的年龄相关缺陷有关。我们将研究遗传过程中线粒体质量控制的机制，以及这一过程如何随年龄变化。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子不随年龄下降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（包括神经元和免疫细胞）衰老的理解，这些细胞是与年龄相关的疾病和衰老的目标。