Mitochondrial inheritance and quality control

不对称细胞分裂，细胞成分的不对称遗传产生两个 具有不同特性和命运的子代细胞对发育是必不可少的。它也是对 维持干细胞和祖细胞，这对组织和器官的更新以及 有机体。我们使用萌芽酵母，酿酒酵母，来研究细胞不对称分裂及其作用 在寿命控制中的这一过程。酿酒酵母细胞不对称分裂的一个后果是母体- 女儿年龄不对称，主要是指女儿的细胞或花蕾早早出生的现象。 与它们母细胞的年龄无关。我们发现，线粒体，已建立的衰老决定因素，是 在酵母细胞分裂过程中不对称遗传的。酵母子细胞继承了功能更强的线粒体， 它们的还原程度更高，膜电位更高，含有更低水平的活性氧。 我们发现，在萌芽酵母中驱动线粒体运动的膜-细胞骨架相互作用 导致更高功能的线粒体从母亲细胞优先传输到子细胞。此外，我们 确定了锚定和保留高功能线粒体的拴系机械的组件 母子细胞。有趣的是，我们发现母细胞中更合适的线粒体的系链 并确定了肌动蛋白细胞骨架在区域特异性中的作用 定位锚和/或极性提示。同样重要的是，我们发现促进Fitter的传承 酵母子细胞的线粒体可以延长寿命和促进健康(晚期生活质量 年龄)。我们将研究1)极性信号，它的调节器，以及锚固机械的新部件，2) 极性因子或其调节因子依赖于细胞骨架定位的机制 线粒体锚定部位，以及3)极性因子、其调节因子和其靶标在寿命中的作用 控制力。在互补性研究中，我们确定了线粒体相关降解的主要作用。 线粒体质量控制途径(MAD)对细胞器中轻度氧化应激的响应。疯了就是 人们对此知之甚少。然而，它类似于ERAD，ERAD是一种识别未折叠的ER蛋白和 将它们重新转移到细胞器的表面，在那里它们被泛素化并被 蛋白酶体。我们将研究1)线粒体内的MAD靶点和成分，2)MAD的作用机制 MAD组分；3)MAD在线粒体质量控制和寿命控制中的作用。虽然 最近的证据表明，非对称遗传几乎只在发育过程中被研究过 线粒体在人类乳腺干细胞中是不对称遗传的，这一过程影响 细胞的命运。此外，MAD成分的缺失会导致人类患上致命的线粒体疾病。因此，我们的 研究将为理解其他类型细胞中的线粒体质量控制过程提供基础 以及能够促进人类健康和寿命的潜在目标。

Asymmetric cell division, the process whereby asymmetric inheritance of cellular components gives rise to two daughter cells that have different characteristics and fates, is essential for development. It is also essential for maintaining stem and progenitor cells, which are critical for tissue and organ renewal and for the lifespan of the organism. We use the budding yeast, Saccharomyces cerevisiae, to study asymmetric cell division and the role of that process in lifespan control. One consequence of asymmetric cell division in S. cerevisiae is mother- daughter age asymmetry, the phenomenon whereby daughter cells or buds are born young, largely independent of the age of their mother cells. We find that mitochondria, established aging determinants, are asymmetrically inherited during yeast cell division. Yeast daughter cells inherit higher-functioning mitochondria, which are more reduced, have higher membrane potential and contain lower levels of reactive oxygen species. We find that the membrane-cytoskeleton interactions that drive mitochondrial movement in budding yeast result in preferential transport of higher-functioning mitochondria from mother to daughter cell. Moreover, we identified components of the tethering machineries that anchor and retain higher-functioning mitochondria in mother and daughter cells. Interestingly, we find that the tether for fitter mitochondria in mother cells responds to previously unappreciated polarity cues and identified a role for the actin cytoskeleton in region-specific localization of the anchor and/or polarity cues. Equally important, we find that promoting inheritance of fitter mitochondria by yeast daughter cells can extend lifespan and promote healthspan (quality of life in advanced age). We will study 1) the polarity cues, its regulators, and new components of the anchorage machinery, 2) the mechanism underlying cytoskeleton-dependent localization of the polarity factor or its regulators to mitochondrial anchorage sites, and 3) the role of the polarity factor, its regulators, and its targets in lifespan control. In complementary studies, we identified a major role for the mitochondria-associated degradation pathway (MAD) in mitochondrial quality control in response to mild oxidative stress in the organelle. MAD is poorly understood. However, it is similar to ERAD, a pathway that recognizes unfolded ER proteins and retrotranslocates them to the surface of the organelle, where they are ubiquitinated and degraded by the proteasome. We will study 1) MAD targets and components within mitochondria, 2) the mechanism of action of MAD components, and 3) the role of MAD in mitochondrial quality control and lifespan control. Although asymmetric inheritance has been studied almost exclusively during development, recent evidence indicates that mitochondria are asymmetrically inherited in human mammary stem-like cells and that this process affects cell fate. Moreover, deletion of a MAD component results in fatal mitochondrial disease in humans. Thus, our studies will provide a foundation for understanding mitochondrial quality control processes in other cell types and potential targets that can promote human health and lifespan.