The Perception of Mitochondrial Stress in Receiving Cells

描述（由申请人提供）：最近发现神经元细胞ETC信号的减少足以延长秀丽隐杆线虫的寿命。研究还发现，这种影响取决于线粒体应激反应或UPRmt的一个重要组成部分的活性。然而，这种寿命延长的基本机制以及信号是如何发送和感知的，目前还不清楚。此外，线粒体在细胞内稳态和能量产生中的重要作用表明，它可能作为随机的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这种系统响应随机变化所显示的紧急特性的原因，并且/或者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）。进一步的假设是，它可以预测UPRmt和应激反应途径之间的协方差，目前认为它们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。

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.