Mitochondrial-cytoskeletal interactions and aging

描述(申请人提供)：人类婴儿出生时很小，与父母的年龄无关。早期的研究表明，酵母中的子细胞也是年轻的，具有完整的复制寿命，与母细胞的年龄无关。芽期酵母中母子年龄不对称的发现导致了老化决定因素在酵母细胞分裂过程中不对称分布的假设。我们得到的证据表明：1)单个细胞内线粒体活性氧种(ROS)存在异质性，2)线粒体ROS较低，因此更适合子代细胞的遗传，3)遗传过程中线粒体质量控制的缺陷扰乱了母子年龄的不对称。这些研究表明，低ROS的线粒体是导致子代细胞健康和母女年龄不对称的年轻因素。我们发现，注定要遗传给子代细胞的线粒体经历了依赖肌动蛋白的从母细胞到子代细胞的移动，以及子代细胞内依赖肌动蛋白的锚定。我们还发现了一种基于肌动蛋白的机制，使货物向相反的方向移动，从芽细胞到母细胞。我们认为，这些机制有助于线粒体在遗传过程中的质量控制，进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子年龄不对称决定因素的分离有关，包括清除芽中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，我们发现肌动蛋白缆索--负责这些分离事件的结构--在组织和功能上经历了与年龄相关的衰退。我们认为，随着年龄的增长，肌动蛋白组织和功能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的线粒体，这反过来又导致与年龄相关的细胞功能障碍和母女年龄不对称的丧失。线粒体通过其在有氧能量动员、细胞代谢控制和ROS产生方面的功能，已成为寿命的中央调节因素。肌动蛋白细胞骨架在神经元、免疫细胞和酵母中的极化分泌部位与线粒体的丰富有关。此外，肌动蛋白的年龄相关性下降与骨骼肌功能、上皮愈合和T细胞激活的年龄相关性缺陷有关。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年龄下降，以及保护肌动蛋白和线粒体质量控制因素不随年龄下降的干预措施是否会影响寿命控制。拟议的研究将扩大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，这些细胞是年龄相关疾病和衰老的靶标。

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.