Mitochondrial inheritance and quality control

线粒体遗传和质量控制

• 批准号: 9901539
• 负责人: Liza A Pon
• 金额: $ 49.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901539
• 关键词: Actins; Affect; Age; Aging; Apoptosis; Cell Division Process; Cell division; Cell physiology; Cells; Characteristics; Cues; Cytoskeleton; Daughter; Defect; Degradation Pathway; Development; Disease; Elderly; Endoplasmic Reticulum Degradation Pathway; Estrogen receptor positive; Foundations; Health; Heart Diseases; Human; Inherited; Link; Longevity; Mammary gland; Membrane; Membrane Potentials; Mitochondria; Mitochondrial Diseases; Mitochondrial Inheritance; Mothers; Movement; Muscular Dystrophies; Neurodegenerative Disorders; Organ; Organelles; Organism; Oxidative Stress; Pathway interactions; Process; Proteins; Quality Control; Quality of life; Reactive Oxygen Species; Role; Saccharomyces cerevisiae; Saccharomycetales; Signal Transduction; Site; Surface; Tissues; Yeasts; cell type; daughter cell; fitness; healthspan; multicatalytic endopeptidase complex; response; stem cells; stem-like cell

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.

不对称细胞分裂，细胞成分不对称遗传的过程产生了两个 具有不同特征和命运的子细胞对于发展至关重要。这也是必不可少的 维持茎和祖细胞，这对于组织和器官更新至关重要，并且寿命 生物。我们使用发芽的酵母酿酒酵母来研究不对称的细胞分裂和角色 在寿命控制中的过程。酿酒酵母中不对称细胞分裂的结果是母亲 女儿年龄不对称，这是女儿细胞或芽年轻的现象，在很大程度上很大 独立于母细胞的年龄。我们发现线粒体已建立的衰老决定因素是 在酵母细胞分裂期间不对称遗传。酵母子细胞继承了高功能的线粒体， 较低的膜电位较高，并且含有较低水平的活性氧。 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 导致优先运输高功能的线粒体从母亲到子细胞。而且，我们 鉴定出锚定和保留较高功能的线粒体的束缚机械组件 母子和女儿细胞。有趣的是，我们发现母细胞中拟合纤维线粒体的系绳有反应 以前未接受的极性提示，并确定了肌动蛋白细胞骨架特异性的作用 锚定和/或极性提示的定位。同样重要的是，我们发现促进fitter的继承 酵母子细胞的线粒体可以延长寿命并促进HealthSpan（高级生活质量 年龄）。我们将研究1）锚固机械的极性提示，其调节器和新组件，2） 极性因子或其调节剂的基础细胞骨架依赖性定位的机制 线粒体锚固位点，3）极性因子，其调节剂及其目标在寿命中的作用 控制。在互补研究中，我们确定了线粒体相关降解的主要作用 线粒体质量控制中的途径（疯狂），以响应细胞器中的轻度氧化应激。疯了 理解不佳。但是，它与Erad相似，Erad是一种识别出现的ER蛋白和 将它们转换到细胞器的表面，在那里它们被泛素化并被降解 蛋白酶体。我们将研究1）线粒体内的疯狂目标和组件，2） 疯狂的组件和3）疯狂在线粒体质量控制和寿命控制中的作用。虽然 最新证据表明，在开发过程中几乎完全研究了不对称的遗传 线粒体是在人类乳样细胞中不对称遗传的，并且此过程会影响 细胞命运。此外，删除疯狂成分会导致人类致命的线粒体疾病。因此，我们的 研究将为理解其他细胞类型的线粒体质量控制过程提供基础 以及可以促进人类健康和寿命的潜在目标。