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

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.

该奖项的全部或部分资金根据《2021 年美国救援计划法案》（公法 117-2）提供。该项目重点研究控制线粒体功能的生化机制，线粒体是细胞内的特殊隔室，对于能量产生和细胞代谢至关重要。线粒体含有自己的小基因组（线粒体 DNA），其中包含细胞能量生产所需的少量蛋白质的遗传指令。细胞如何调节线粒体基因组的表达以响应不断变化的能量需求尚不清楚。这项工作将探索已知与线粒体 DNA 相互作用的蛋白质是否可以作为营养可用性的传感器，进而控制线粒体基因表达，从而深入了解控制哺乳动物细胞功能的基本机制。该项目还将通过本科生研究人员的培训、实施为短期课程设计的通用生物化学实验室课程以及将研究纳入高级生物化学实验课程，扩大希望学院的生物化学本科生培训。该项目的研究和教育目标有望通过为生物化学本科生研究提供机会来产生广泛的社会影响。这些机会将提高科学学生的保留率，从而有助于充实科学劳动力。美国救援计划对该项目的资助将在研究人员职业生涯的关键阶段提供支持。该研究将重点关注一碳代谢和氧化还原代谢与线粒体基因组调控之间的交叉点。为了使线粒体正常发挥作用，这些细胞器依赖于它们自己的基因组中携带的遗传指令以及核基因组中携带的遗传指令。核 DNA 携带 2000 个线粒体蛋白质组中大部分的指令，包括许多与线粒体 DNA 相关的核蛋白。将结合生物化学和细胞生物学方法来研究参与甲酸和 NADPH 代谢的四种核蛋白。这些酶与 mtDNA 结合的性质和效果尚不清楚。由于甲酸和 NADPH 水平反映了细胞的代谢状态，因此该研究将调查这些酶传递能量状态信号以控制线粒体基因组动力学和能量产生的假设。该研究有望在线粒体和哺乳动物细胞内的调控机制方面取得重大进展。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。