Regulated Mitochondrial Morphology

摘要 受调控的线粒体形态 线粒体网具有数量惊人的基本细胞功能，包括 呼吸能量的产生，关键代谢物的合成代谢产物，以及调节细胞死亡。 突变、损伤和感染会降低线粒体的活性，并造成损伤或功能障碍 线粒体在很长一段时间内即使不是致病因素，也越来越被认为是起作用的因素 越来越多的疾病。在老化、损伤或患病的细胞中最常见的缺陷 是相互连接的网状结构分解成超碎裂的细胞器单位，这些细胞器单位失去了 化学势和它们基因组的完整性。疾病中的超分裂现象观察 环境引起了临床对线粒体裂变机械的特定抑制物的兴趣 改善一系列疾病：从慢性神经变性和某些癌症到更严重的疾病 心脏病发作和中风等损伤--在动物模型中进行的概念验证研究前景看好。 然而，进展缓慢，部分原因是我们不了解分子机制。 来管理线粒体的分裂。我们实验室最新的生化突破-结合 电子冷冻显微镜或低温电子显微镜的分辨率革命终于让我们做好了解决 以前所未有的细节驱动这些裂变机器的机制。我们建议确定 控制表面裂变机器招募和组装的结构机制 通过专门化受体(Aim1)的活性改变线粒体。我们进一步建议确定 利用鸟嘌呤核苷酸中存在的化学能的变构蛋白质运动 对线粒体管进行机械的收缩工作(目标2)。最后，我们建议 确定翻译后修饰(包括磷酸化和SUMO化)如何调整或 关闭裂变机器的活动(目标3)。共同努力，实现这些目标将 提供对这些基本蜂窝机器如何工作的新的独特见解，并将使 新一代结构导向研究，以确定和表征新的治疗机会。

Abstract Regulated Mitochondrial Morphology The mitochondrial reticulum performs an astonishing number of essential cellular functions, including respiratory energy production, anabolic production of critical metabolites, and regulated cell death. Mutations, injuries, and infections degrade mitochondrial activity; and damaged or dysfunctional mitochondria are increasingly recognized as contributing if not causative factors for a long and still growing list of diseases. The most commonly observed defect seen in aging, injured, or diseased cells is a breakdown of the inter-connected reticulum into hyper-fragmented organelle units that lose their chemical potential and the integrity of their genomes. The observation of hyper-fission in disease settings generated clinical interest in specific inhibitors of the mitochondrial fission machinery to ameliorate a range of illness: from chronic neurodegeneration and certain cancers to more acute injuries like heart attack and stroke—with promising proof-of-concept studies in animal models. Progress has been slow, however, in part because we do not understand the molecular mechanisms that govern mitochondrial fission. Recent biochemical breakthroughs in our lab—in combination with the resolution revolution in electron cryo-microscopy or cryoEM—have finally prepared us to resolve the mechanisms that drive these fission machines in unprecedented detail. We propose to determine the structural mechanisms that govern recruitment and assembly of the fission machine on the surface of mitochondria through the activity of specialized receptors (Aim1). We further propose to determine the allosteric protein motions that harness the chemical energy present in guanine nucleotides to perform mechanical, constricting work on mitochondrial tubules (Aim 2). Finally, we propose to determine how post-translational modifications—including phosphorylation and SUMOylation—tune or turn off the activity of the fission machinery (Aim 3). Together, accomplishing these objectives will provide new and unique insights into how these fundamental cellular machines work and will enable a new generation of structure-guided studies to identify and characterize novel therapeutic opportunities.