The Perception of Mitochondrial Stress in Receiving Cells

描述(申请人提供)：最近发现神经细胞中ETC信号的减少足以延长线虫的寿命。研究还发现，这种效应依赖于线粒体应激反应(UPRmt)的一个重要组成部分的活性。然而，目前还不清楚这种寿命延长发生的基本机制，也不知道信号是如何发送和感知的。此外，线粒体在细胞内稳态和能量产生中所起的重要作用表明，它可能作为随机内在或外在变量的反应性传感器，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中表现出的响应随机变化的紧急特性的原因，和/或可能在协调非线粒体应激反应途径的激活方面发挥重要作用。关于基因修饰将降低线粒体功能随机变异能力的预测，最终将对生物体的适应性产生负面影响。这样的假设与最近的证据是一致的，这些证据表明，有害的突变实际上会降低基因表达对小环境变化(表型稳健性的丧失)的敏感性。另一个假设是，它可以预测UPRmt和应激反应通路之间的协变，目前人们认为它们在不同的调控网络中发挥作用，并试图发现这种协变发生的潜在机制。 公共卫生相关性：线粒体和细胞之间的内生共生关系最初为细胞提供了必要的能量，以允许分化并最终进入一种特殊器官和组织可以进化的复杂状态。20亿年后，由器官、组织和细胞组成的复杂网络组成的整个有机体，完全依赖线粒体的能量功能。面对日益复杂的环境，真核细胞现在花费了相当数量的线粒体衍生能量来试图协调动态平衡，并将随机事件扰乱整个生物体功能导致疾病的可能性降至最低。

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.