Mitochondrial inheritance and quality control

线粒体遗传和质量控制

• 批准号: 9277129
• 负责人: Liza A Pon
• 金额: $ 46.73万
• 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/9277129
• 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; 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; Stem cells; Surface; Tissues; Yeasts; cell type; daughter cell; fitness; multicatalytic endopeptidase complex; response; 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，细胞成分的不对称遗传产生两个细胞的过程。 具有不同特征和命运的子细胞对发育至关重要。这也是必不可少的， 维持干细胞和祖细胞，这对组织和器官的更新以及生命周期至关重要。 有机体我们使用芽殖酵母，酿酒酵母，研究细胞不对称分裂和作用， 在寿命控制中的作用。S.酿酒厂是母亲， 子细胞年龄不对称，即子细胞或芽出生时很年轻， 与母细胞的年龄无关。我们发现，线粒体，建立老化的决定因素， 在酵母细胞分裂期间不对称地遗传。酵母子细胞继承了功能更强的线粒体， 其被更多地还原，具有更高的膜电位并且含有更低水平的活性氧物质。 我们发现在芽殖酵母中驱动线粒体运动的膜-细胞骨架相互作用 导致高功能线粒体从母细胞到子细胞的优先运输。而且我们 确定了拴系机制的组成部分，该机制锚定并保留了高功能的线粒体， 母细胞和子细胞有趣的是，我们发现，在母细胞中， 以前未被重视的极性线索，并确定了肌动蛋白细胞骨架在区域特异性 锚的定位和/或极性提示。同样重要的是，我们发现， 线粒体的酵母子细胞可以延长寿命，促进健康（生活质量在先进的 年龄）。我们将研究1）极性线索，其调节器，和锚定机械的新组件，2） 极性因子或其调节因子依赖于细胞凋亡的定位机制， 线粒体锚定位点，和3）极性因子的作用，其调节剂，以及其在寿命中的目标 控制在补充研究中，我们确定了一个主要的作用， 在线粒体质量控制中，MAD途径对细胞器中的轻度氧化应激作出反应。MAD是 不太了解。然而，它与ERAD相似，ERAD是一种识别未折叠ER蛋白的途径， 将它们逆向转运到细胞器的表面，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MAD靶点和组分，2） MAD组分，以及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，不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，这一过程影响了 细胞命运此外，MAD组分的缺失导致人类的致命线粒体疾病。所以我们 研究将为理解其他细胞类型中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。