Investigating the Molecular Mechanisms of Mitochondrial Calcium Uptake in Caenorhabditis elegans

项目摘要 神经退行性疾病造成的巨大社会负担，强调了 确定促进疾病的潜在病理机制。钙信号的失调 并且线粒体功能被破坏是在神经变性疾病中观察到的常见症状， 包括肌萎缩性侧索硬化症、帕金森病和阿尔茨海默病。然而，底层 这些缺陷在介导病理学中的作用，如果它们相互影响以促进疾病， 明白除了它们在能量产生中的作用之外，线粒体的功能是隔离大量涌入的 细胞溶质钙并作为细胞器钙缓冲剂。然而，钙的流入， 线粒体还刺激线粒体的活性，如三羧酸循环、氧化还原、氧化还原和氧化还原。 磷酸化，活性氧的产生，它也可以引发细胞死亡。的 遗传学保守的线粒体钙单向转运体复合物介导钙的摄取进入线粒体。 线粒体随着线粒体钙单向转运体复合物组分的分子鉴定， 目前的许多研究表明，线粒体钙稳态的改变在细胞凋亡中起着重要作用， 促进神经退化这些数据强调了理解这些机制的重要性， 介导线粒体钙稳态。在这里，我们建议利用遗传的顺从性和简单性， 梭1）询问线粒体钙单向转运体的四个核心组分的作用 在体内模型系统中建立线粒体钙单向转运体复合物的基础 功能和2）发现参与线粒体钙内流的新基因产物。从这些 研究，我们的目标是提高我们对线粒体钙摄取和稳态的理解， 为开发治疗神经退行性疾病的新治疗策略提供重要指导 疾病

PROJECT SUMMARY The enormous societal burden caused by neurodegenerative disorders, stresses the importance of determining the underlying pathological mechanisms that promote disease. Both deregulated calcium signaling and disrupted mitochondrial function are a common symptom observed in neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. However, the underlying role these defects have in mediating pathology and if they impact each other to promote disease is not fully understood. In addition to their role in energy production, mitochondria function to sequester large influxes of cytosolic calcium and act as an organellular calcium buffer. However, the influx of calcium into the mitochondrial also stimulates the activity of the mitochondria, such as the tricarboxylic acid cycle, oxidative phosphorylation, the production of reactive oxygen species, and it can also trigger cell death. The phylogenetically conserved mitochondrial calcium uniporter complex mediates the uptake of calcium into the mitochondria. With the recent molecular identification of mitochondrial calcium uniporter complex components, many current studies have implicated altered mitochondrial calcium homeostasis as having a fundamental role in promoting neurodegeneration. These data highlight the importance of understanding the mechanisms that mediate mitochondrial calcium homeostasis. Here, we propose to utilize the genetic amenability and simplicity of C. elegans to 1) interrogate the role of the four core components of the mitochondrial calcium uniporter complex in an in vivo model system to establish a foundation of mitochondrial calcium uniporter complex function and to 2) discover new gene products that are involved in mitochondrial calcium influx. From these studies, our goals are to improve our understanding of mitochondrial calcium uptake and homeostasis and to provide critical guidance for the development of novel therapeutic strategies for treating neurodegenerative diseases.