The Perception of Mitochondrial Stress in Receiving Cells

接收细胞中线粒体应激的感知

• 批准号: 8258677
• 负责人: Andrew G Dillin
• 金额: $ 46.46万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258677
• 关键词: Address; Affect; Age of Onset; Aging; Aging-Related Process; Animals; Biogenesis; Boxing; Caenorhabditis elegans; Cell Nucleus; Cell model; Cells; Communication; Complex; Cytosol; Disease; Distal; Double-Stranded RNA; Electron Transport; Environment; Eukaryotic Cell; Event; Exposure to; Gene Expression; Genetic; Genetic Epistasis; Head; Homeostasis; Intestines; Longevity; Mitochondria; Mitochondrial DNA; Modification; Morphology; Mutation; Nature; Nematoda; Nervous system structure; Neurodegenerative Disorders; Neurological observations; Neurons; Organ; Organism; Oxidation-Reduction; Pathway interactions; Perception; Peripheral; Play; Ploidies; Population; Predisposition; Production; Property; Proteins; RNA Interference; Receptor Signaling; Respiration; Role; Signal Pathway; Signal Transduction; Solid; Sorting - Cell Movement; Stress; System; Techniques; Tissues; Toxic Environmental Substances; Translations; Up-Regulation; Variant; Whole Organism; biological adaptation to stress; cell type; complex IV; environmental change; experience; extracellular; fitness; genome wide association study; innovation; mitochondrial dysfunction; programs; promoter; protein folding; response; sensor

DESCRIPTION (provided by applicant): It was recently discovered that reduced ETC signaling in neuronal cells is sufficient to extend the lifespan of C. elegans. It was also found that this effect is dependent upon the activity of an essential component of the mitochondrial stress response or UPRmt. It is not yet understood, however, the fundamental mechanisms by which this life span extension occurs or how the signal is sent and perceived. Moreover, the essential role that the mitochondrion has in cellular homeostasis and energy production suggests that it may act as a reactive sensor of random intrinsic or extrinsic variables capable of influencing an organism's susceptibility to disease. Changes within the mitochondria thus also might be responsible for the emergent properties displayed in such a system in response to stochastic changes, and/or may play a significant role in coordinating the activation of non-mitochondrial stress response pathways. A prediction that genetic modifications will decrease the capacity for stochastic variation in mitochondrial function will ultimately negatively affect the fitness of the organism. Such a hypothesis is in keeping with recent evidence suggesting that deleterious mutations actually decrease the sensitivity of gene expression in response to small environmental changes (a loss of phenotypic robustness). A further hypothesis is it may predict co-variance between the UPRmt and stress response pathways, currently thought to act in distinct regulatory networks, and seek to discover the potential mechanisms by which this co-variance occurs. PUBLIC HEALTH RELEVANCE: The endosymbiotically-derived relationship between the mitochondria and cell initially provided the cell with the energy necessary to allow for differentiation and to eventually enter into a state of complexity in which specialized organs and tissues could evolve. Two billion years later, whole organisms composed of complex networks of organs, tissues, and cells, are utterly dependent upon mitochondria for their energetic functions. In the face of an increasingly complex environment, the eukaryotic cell now spends a considerable amount of mitochondrial-derived energy in an attempt to coordinate homeostasis and to minimize the potential for stochastic events to disrupt whole organism function leading to disease.

描述（由申请人提供）：最近发现，神经元细胞中ETC信号传导的减少足以延长C.优美的还发现这种作用依赖于线粒体应激反应或UPRmt的重要组分的活性。然而，目前还不清楚这种寿命延长发生的基本机制，或者信号是如何发送和感知的。此外，在细胞内稳态和能量产生中的重要作用表明，它可以作为随机内在或外在变量的反应传感器，能够影响生物体对疾病的易感性。因此，线粒体内的变化也可能是负责在这样的系统中显示的响应于随机变化的涌现特性，和/或可能在协调非线粒体应激反应途径的激活中发挥重要作用。预测遗传修饰将降低线粒体功能随机变异的能力，最终将对生物体的适应性产生负面影响。这种假设与最近的证据一致，这些证据表明有害突变实际上降低了基因表达对微小环境变化的敏感性（表型稳健性的丧失）。另一个假设是，它可以预测UPRmt和应激反应途径之间的协方差，目前认为在不同的调节网络中起作用，并试图发现这种协方差发生的潜在机制。 公共卫生关系：线粒体和细胞之间的内共生关系最初为细胞提供了分化所需的能量，并最终进入一种复杂的状态，在这种状态下，专门的器官和组织可以进化。二十亿年后，由器官、组织和细胞组成的复杂网络组成的整个生物体完全依赖线粒体来发挥其能量功能。面对日益复杂的环境，真核细胞现在花费大量的细胞来源的能量，试图协调体内平衡，并尽量减少随机事件破坏整个生物体功能导致疾病的可能性。