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

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。这个项目的重点是控制线粒体功能的生化机制，线粒体是细胞内对能量产生和细胞新陈代谢至关重要的特殊间隔。线粒体包含它们自己的小基因组(线粒体DNA)，其中包含细胞能量产生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，以应对不断变化的能量需求，在很大程度上是未知的。这项工作将探索已知的与线粒体DNA相互作用的蛋白质是否作为营养供应的传感器，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生研究人员，实施为短课时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室课程，来扩大希望学院的生物化学本科培训。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而产生广泛的社会影响。这些机会将改善留住理科学生的机会，这些学生将有助于充实科学大军。美国救援计划资助的这个项目将支持这位研究人员在她职业生涯的关键阶段。研究将集中在单碳代谢和氧化还原代谢与线粒体基因组调控之间的交集。为了线粒体的正常运作，这些细胞器依赖于它们自己基因组中携带的遗传指令，以及核基因组中携带的那些遗传指令。核DNA携带着2000个成员的线粒体蛋白质组的大部分指令，包括一些被证明与线粒体DNA相关的类核蛋白。我们将结合生物化学和细胞生物学的方法来研究与甲酸盐和NADPH代谢有关的四种核蛋白。这些酶与线粒体DNA结合的性质和作用尚不清楚。由于甲酸和NADPH水平反映了细胞的新陈代谢状态，研究将调查这两种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。这项研究承诺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。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.