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严格调节。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。本提案的目的是研究核/线粒体通信现象及其在线粒体数量调节中的作用。工作的假设是，线粒体已经进化出了与细菌祖先的群体感应途径非常相似的途径，以传达细胞中增加或减少线粒体含量的需要。三个标准将用于确定是否群体感应类型的信号通路已在线粒体中保守。首先是线粒体产生并释放了一种类似群体感应的信号分子。这种分子的检测方法类似于在细菌中分离群体感应分子的方法。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。第三个标准是线粒体衍生分子在整个细胞系统中引起或抑制线粒体生物发生的能力。线粒体含有类似于细菌群体感应的途径，这一发现将使我们更全面地了解线粒体数量和细胞代谢的调节，并最终使我们更好地理解线粒体数量很重要的许多人类疾病，包括但不限于癌症、衰老、线粒体DNA疾病、糖尿病和肥胖。此外，鉴定线粒体生物发生的脂质信号将为这些疾病的药物干预打开大门。

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.