Mitochondrial inner membrane architecture in skeletal muscle pathophysiology

项目摘要 肌肉是一种收缩组织，能产生对动物生存至关重要的力量和运动。分子和细胞 管理其结构和功能完整性的机制尚未得到很好的理解。选择性功能障碍和 在以线粒体为特征的疾病条件下观察到神经肌肉组织的退化。 异常的，强调线粒体对肌肉的功能和完整性的特殊重要性 纸巾。线粒体在细胞生物能量学以及细胞的其他基本方面发挥着重要作用。 生理学。对骨骼的结构和功能的完整性至关重要的线粒体过程 肌肉，以及这些过程在健康和疾病中是如何调节的，还没有明确的定义。它正在成为 越来越清楚的是，骨骼发育、功能和维持的基本机制 肌肉在后生动物中是保守的。因此，遗传模式生物将会有重要的意义 有助于我们理解这些机制。在我们之前的研究中，我们使用果蝇作为一种 模型显示NumB/Notch信号和不对称祖细胞分裂在 肌肉发育，以及PINK1/Parkin指导的骨骼肌维护中的线粒体质量控制。我们 也使用苍蝇神经肌肉接头(NMJ)作为模型来剖析与年龄相关的突触机制。 相关的神经退行性疾病。在我们最新的研究中，我们发现蛋白质质量控制在 线粒体膜间隙(IMS)对骨骼肌的功能和维持具有重要意义。我们发现 源于GGGGCC(G4C2)六核苷酸重复序列非常规翻译的二肽重复序列(Dprs) C9ORF72是肌萎缩侧索硬化症(ALS)最常见的遗传原因，称为C9ALS， 通过改变IMS蛋白平衡和内膜(IM)结构来破坏线粒体的功能。我们的基因 修饰物筛选确定了一些信号通路，以减轻这种ALS相关的肌肉病理。目标是 这项建议的目的是使用蛋白质组学、分子遗传学和细胞生物学工具来定义 已确定的遗传途径，努力实现对线粒体调节和功能的整体看法 IM架构在骨骼肌功能和维护中的作用。两个具体目标将帮助我们实现这一目标。在AIM 1，我们将研究c9ALS病基因产物如何破坏肌肉线粒体的分子机制。 IMS/IM的结构和功能。新的遗传工具将被用来进行超微结构研究，并发现 DPR在这些结构中的相互作用。在目标2中，我们将描述细胞质量控制机制 通过抑制DPR的合成或促进其代谢来维持IMS/IM的完整性。这些品质的作用 在正常衰老过程中维持线粒体和骨骼肌结构和功能的控制机制 也要接受检查。这些研究将极大地促进我们对线粒体在 维持骨骼肌的结构和功能。这项研究的结果有望为 治疗肌萎缩侧索硬化症和骨质疏松症等疾病的新型合理的肌肉靶向药物。

Project Summary Muscle is a contractile tissue that generates forces and motions vital for animal survival. The molecular and cellular mechanisms governing its structural and functional integrity are not well understood. Selective dysfunction and degeneration of neuromuscular tissues have been observed in disease conditions featuring mitochondrial abnormality, emphasizing the particular importance of mitochondria to the functionality and integrity of muscle tissues. Mitochondria play important roles in cellular bioenergetics as well as other essential aspects of cellular physiology. The mitochondrial processes that are essential for the structural and functional integrity of skeletal muscle, and how these processes are regulated in health and disease are poorly defined. It is becoming increasingly clear that fundamental mechanisms underlying the development, function, and maintenance of skeletal muscle are conserved across metazoans. Thus genetic model organisms are poised to make significant contributions to our understanding of these mechanisms. In our previous studies, we have used Drosophila as a model to demonstrate the importance of Numb/Notch signaling and asymmetric progenitor cell division during muscle development, and PINK1/Parkin-directed mitochondrial quality control in skeletal muscle maintenance. We have also used the fly neuromuscular junction (NMJ) as a model to dissect synaptic mechanisms involved in age- related neurodegenerative diseases. In our most recent studies, we have found that protein quality control in the mitochondrial intermembrane space (IMS) is important for skeletal muscle function and maintenance. We found that dipeptide repeats (DPRs) derived from unconventional translation of the GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) called c9ALS, disrupt mitochondrial function by altering IMS proteostasis and inner membrane (IM) architecture. Our genetic modifier screens identified a number of signaling pathways in mitigating this ALS-related muscle pathology. The goal of this proposal is to use proteomic, molecular genetic, and cell biological tools to define the mechanism of action of the identified genetic pathways, in an effort to achieve a holistic view of the regulation and function of mitochondrial IM architecture in skeletal muscle function and maintenance. Two Specific Aims will help us reach this goal. In Aim 1, we will examine the molecular mechanisms of how c9ALS disease gene product disrupts muscle mitochondrial IMS/IM structure and function. Novel genetic tools will be used to perform ultrastructural studies and find the interactome of DPR within these structures. In Aim 2, we will delineate the cellular quality control mechanisms that maintain IMS/IM integrity by restraining the synthesis or promoting the metabolism of DPR. The role of these quality control mechanisms in maintaining mitochondrial and skeletal muscle structure and function during normal aging will also be examined. These studies will significantly advance our understanding of the role of mitochondria in maintaining skeletal muscle structure and function. Results from this study promise to inform the development of novel and rational muscle-targeting medicine for ALS and conditions such as sarcopenia.