CAREER: Mitochondrial Genome Regulation By Nucleoid Proteins Involved in Redox Sensing and One Carbon-Metabolism

职业：参与氧化还原传感和一碳代谢的核蛋白对线粒体基因组的调控

• 批准号: 2141375
• 负责人: Kristin Dittenhafer-Reed
• 金额: $ 54万
• 依托单位: Hope College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2141375&HistoricalAwards=false
• 关键词: CAREER; Mitochondrial; Genome; Regulation; Nucleoid; CAREER; Mitochondrial; Genome; Regulation; Nucleoid

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). This project focuses on biochemical mechanisms that control the function of mitochondria, specialized compartments within cells that are central to energy production and cell metabolism. Mitochondria contain their own small genome (mitochondrial DNA) that contains the genetic instructions for a small number of proteins required for cellular energy production. How cells regulate the expression of the mitochondrial genome in response to changing energetic needs is largely unknown. This work will explore if proteins known to interact with mitochondrial DNA serve as sensors of nutrient availability and in turn control mitochondrial gene expression, providing insight into fundamental mechanisms that control mammalian cell function. The project will also expand undergraduate training in biochemistry at Hope College through the training of undergraduate researchers, the implementation of a general biochemistry lab curriculum designed for short class periods, and the incorporation of the research in an upper-level biochemistry lab course. The research and educational objectives of the project promise to have broad societal impacts by providing opportunities for undergraduate research in biochemistry. These opportunities will improve the retention of students in science who will help populate the scientific workforce. American Rescue Plan funding of this project will support the investigator at a critical stage in her career.The research will focus on the intersection between one-carbon metabolism and redox metabolism with mitochondrial genome regulation. For mitochondria to function properly, these organelles rely on genetic instructions carried within their own genome, as well as those carried in the nuclear genome. Nuclear DNA carries the instructions for the majority of the 2000-member mitochondrial proteome, including a number of nucleoid proteins which are shown to associate with mitochondrial DNA. A combination of biochemical and cell biology approaches will be used to study four nucleoid proteins involved in formate and NADPH metabolism. The nature and effect of the association of these enzymes with mtDNA is unknown. As formate and NADPH levels reflect the metabolic state of the cell, the research will investigate the hypothesis that these enzymes relay signals of energetic status to control mitochondrial genome dynamics and energy production. The research promises to provide significant advances related to regulatory mechanisms within the mitochondria and mammalian cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项是根据2021年《美国救援计划法》（公法117-2）全部或部分资助的。该项目的重点是控制线粒体功能的生化机制，即在能量生产和细胞代谢核心的细胞内专门的隔室。线粒体包含自己的小基因组（线粒体DNA），其中包含针对细胞能量产生所需的少量蛋白质的遗传指示。细胞如何响应不断变化的能量需求而调节线粒体基因组的表达是未知的。这项工作将探讨是否已知与线粒体DNA相互作用的蛋白质是养分的传感器，进而控制线粒体基因的表达，从而深入了解控制哺乳动物细胞功能的基本机制。该项目还将通过培训本科研究人员的培训，为短班级时期设计的一般生物化学实验室课程的实施以及在高级生物化学实验室课程中纳入研究，从而扩大希望学院生物化学的本科培训。该项目的研究和教育目标有望通过为生物化学的本科研究提供机会，从而产生广泛的社会影响。这些机会将改善学生在科学方面的保留，这些科学将有助于填充科学劳动力。该项目的美国救援计划资金将在其职业生涯的关键阶段支持研究人员。该研究将重点介绍一种碳代谢与线粒体基因组调节的相交。为了使线粒体正常运行，这些细胞器依赖于自己基因组中携带的遗传指示以及在核基因组中携带的遗传指示。核DNA携带了2000年成员的大多数线粒体蛋白质组的说明，其中包括许多与线粒体DNA相关的核苷蛋白。生化和细胞生物学方法的组合将用于研究参与甲酸和NADPH代谢的四种核苷蛋白。这些酶与mtDNA的关联的性质和影响尚不清楚。由于甲酸盐和NADPH水平反映了细胞的代谢状态，因此研究将研究这些酶传递能量状态的信号以控制线粒体基因组动力学和能量产生的假设。该研究有望提供与线粒体和哺乳动物细胞内的监管机制有关的重大进展。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响审查标准，认为值得通过评估来获得支持。