Coordinating mitochondrial network expansion and longevity via the Integrated Stress Response (ISR)

项目摘要 线粒体功能在正常衰老过程中下降，在与年龄相关的疾病中加速，如 帕金森氏症和阿尔茨海默氏症。因此，了解细胞和生物体如何调节线粒体网络 在生长过程中扩张以满足细胞特定要求，并在 衰老，是限制与线粒体功能障碍相关的病理和延长 寿命。我们发表的研究结果表明，线粒体网络的扩张发生在 发育是合成高表达的线粒体蛋白和ATFS-1的一种紧急性质。 依赖于线粒体UPR的激活。增加高表达线粒体蛋白的进口流量 从线粒体中排除转录因子ATFS-1，导致核运输和UPRmt激活， 其中包括一个线粒体生物发生计划。这些发现表明蛋白质之间存在相互作用。 合成、线粒体蛋白输入能力和线粒体网络扩张。 在这里，我们研究了被称为整合应激反应的翻译控制通路的作用 (ISR)关于发育和衰老过程中线粒体网络扩张的调节。令人惊讶的是，我们的 初步发现，ISR受损的蠕虫具有更多的线粒体生物量 并延长寿命，这表明了恢复衰老细胞线粒体功能的潜在方法。我们 假设ISR在细胞生长过程中提供两种功能：1)它通过以下途径调节蛋白质合成速率 Eif2α的磷酸化，从而不会压倒网络的组装和扩展；2)增加atfs-1/atf5 表达激活转录程序，以促进线粒体网络的扩展。虽然相当可观 研究表明，ISR在线粒体功能障碍期间是活跃的，ISR的功能输出 与线粒体网络相关的基因目前仍不清楚。我们将在线虫和线虫身上测试这一假设 通过以下目的进行哺乳动物细胞培养： 1.ISR在线虫线粒体网络扩张调控中的作用 2.确定ISR介导的翻译调控对线虫寿命的影响。 3.阐明ISR在哺乳动物细胞建立功能性线粒体网络中的作用。

Project Summary Mitochondrial function declines during normal aging and is accelerated in age-associated diseases such as Parkinson’s and Alzheimer’s. Thus, understanding how cells and organisms regulate mitochondrial network expansion during growth to meet cell-specific requirements, and maintain that mitochondrial network during aging, are essential steps to limiting pathologies associated with mitochondrial dysfunction and prolonging lifespan. Our published findings indicate that the mitochondrial network expansion that occurs during development is an emergent property of the synthesis of highly expressed mitochondrial proteins and ATFS-1- dependent mitochondrial UPR activation. Increased import flux of highly expressed mitochondrial proteins excludes the transcription factor ATFS-1 from mitochondria resulting in nuclear trafficking and UPRmt activation, which includes a mitochondrial biogenesis program. These findings suggest an interplay between protein synthesis, mitochondrial protein import capacity, and mitochondrial network expansion. Here, we examine the role of a translation control pathway known as the Integrated Stress Response (ISR) on the regulation of mitochondrial network expansion during development and aging. Surprisingly, our preliminary findings indicate that worms with an impaired ISR have substantially more mitochondrial biomass and increased longevity, suggesting potential approaches to recover mitochondrial function in aged cells. We hypothesize that the ISR provides two functions during cell growth; 1) it regulates protein synthesis rates via eIF2α phosphorylation so as not to overwhelm network assembly and expansion, and 2) increases ATFS-1/ATF5 expression to activate a transcriptional program to facilitate mitochondrial network expansion. While considerable work has demonstrated that the ISR is active during mitochondrial dysfunction, the functional outputs of the ISR as related to the mitochondrial network remain unclear. We will test this hypothesis in both C. elegans and mammalian cell culture via the following aims: 1. The role of the ISR in regulating mitochondrial network expansion in C. elegans. 2. Determine the impact of ISR-mediated translation regulation on C. elegans longevity. 3. Elucidate the role of the ISR in establishing a functional mitochondrial network in mammalian cells.