Regulated Mitochondrial Morphology

摘要 调节线粒体形态 线粒体网执行惊人数量的基本细胞功能，包括 呼吸能量产生、关键代谢物的合成代谢产生和受调节的细胞死亡。 突变、损伤和感染会降低线粒体的活性; 线粒体被越来越多地认为是贡献，如果不是致病因素， 越来越多的疾病。在衰老、受伤或患病细胞中最常见的缺陷 是相互连接的网状物分解成高度碎片化的细胞器单位， 化学势和基因组的完整性。超裂变在疾病中的观察 在特定的线粒体分裂机制抑制剂的临床兴趣， 改善一系列疾病：从慢性神经变性和某些癌症到更急性的 心脏病发作和中风等损伤-在动物模型中进行了有希望的概念验证研究。 然而，进展缓慢，部分原因是我们不了解分子机制 控制着线粒体分裂我们实验室最近的生物化学突破-结合 电子冷冻显微镜或冷冻EM分辨率革命终于使我们准备好解决 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 控制裂变机器在表面上的补充和组装的结构机制 线粒体通过专门的受体（Aim 1）的活动。我们进一步建议， 利用鸟嘌呤核苷酸中存在的化学能， 对线粒体小管进行机械的收缩工作（目的2）。最后，我们建议 确定翻译后修饰-包括磷酸化和SUMO化-如何调节或 关闭裂变机器的活动（目标3）。共同实现这些目标将 为这些基本的细胞机器如何工作提供了新的和独特的见解，并将使 新一代的结构指导研究，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.