Fatty acid signals as quorum sensing regulators of mitochondrial biogenesis

描述（由申请人提供）：线粒体数量在细胞内受到非常严格的调节。了解线粒体数量和代谢的调节在人类健康和疾病的几乎每个领域都很重要。该提案的目标是研究核/线粒体通讯现象及其在线粒体数量调节中的作用。工作假设是，线粒体已经进化出与其细菌祖先的群体感应途径非常相似的途径，以传达增加或减少细胞中线粒体含量的需要。将使用三个标准来确定群体感应型信号传导途径是否在线粒体中保守。第一个是存在一种由线粒体产生和释放的类群体感应信号分子。该分子将使用类似于为分离细菌中的群体感应分子而建立的方法来检测。第二个标准是线粒体衍生分子驱动线粒体生物发生相关分子转录的能力。第三个标准是细胞来源的分子在整个细胞系统中引起或抑制线粒体生物合成的能力。线粒体含有类似于细菌群体感应的途径的发现将允许更完整地理解细胞中线粒体数量和代谢的调节，并最终导致更好地理解线粒体数量重要的多种人类状况，包括但不限于癌症，衰老，基于线粒体DNA的疾病，糖尿病和肥胖症。此外，线粒体生物发生的基于脂质的信号的鉴定将为这些疾病的药物干预打开大门。 公共卫生相关性：线粒体代谢的失调导致能量产生减少、活性氧（ROS）增加和细胞凋亡改变。这三个因素在许多疾病中发挥作用，包括心脏病、糖尿病、癌症、肥胖和神经退行性疾病，如阿尔茨海默病和帕金森病。该项目的目标是研究细胞调节细胞内线粒体数量的方式，着眼于它们的进化起源。

DESCRIPTION (provided by applicant): Mitochondrial number is very tightly regulated within the cell. Developing an understanding of regulation of mitochondrial number and metabolism is important in almost every area of human health and disease. The goal of this proposal is to investigate the phenomenon of nuclear/mitochondrial communication and its role in regulation of mitochondrial number. The working hypothesis is that mitochondria have evolved pathways very similar to the quorum sensing pathways of their bacterial ancestors to communicate the need to increase or decrease mitochondrial content in the cell. Three criteria will used to determine if a quorum sensing type signaling pathway has been conserved in mitochondria. The first is the presence of a quorum sensing-like signaling molecule produced and released from the mitochondria. This molecule will be detected using methods similar to those established for isolating quorum sensing molecules in bacteria. The second criterion is the ability of mitochondrially derived molecules to drive transcription of mitochondrial biogenesis related molecules. The third criterion is the ability of the mitochondrially derived molecules to cause or suppress mitochondrial biogenesis in a whole cell system. The finding that mitochondria contain a pathway similar to bacterial quorum sensing would allow a more complete understanding of the regulation of mitochondrial number and metabolism in the cell, and could ultimately lead to better understanding of a multitude of human conditions where mitochondrial number is important, including but not limited to cancer, aging, mitochondrial DNA based disease, diabetes, and obesity. In addition, the identification of a lipid based signal for mitochondrial biogenesis would open the door for pharmacological intervention in these diseases. PUBLIC HEALTH RELEVANCE: Dysregulation of mitochondrial metabolism leads to decreased energy production, increased reactive oxygen species (ROS), and altered apoptosis. These three factors play a role in a multitude of diseases, including heart disease, diabetes, cancer, obesity, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The goal of this project is to investigate the way in which cells regulate the amount of mitochondria within a cell, with an eye towards their evolutionary origins.