CAREER: Elucidating the Causal Link Associated with Energy Metabolism and Mitochondrial Ultrastructure

线粒体是亚细胞细胞器，对包括人类在内的植物和动物等所谓高等生物的能量生产至关重要。然而，我们并不完全了解线粒体的组成和结构如何决定它们维持生命的能力。我们确实知道，线粒体中的生化反应被分成被称为嵴的小室，在压力下会被破坏。为了了解这种破坏的原因，该项目将采用先进的显微镜来可视化线粒体结构细节和分子方法来模拟破坏的线粒体代谢。该项目将为高中生和教师提供教育经验，并为本科生和研究生提供研究经验，他们将学习如何通过实验将理论概念联系起来，从而产生线粒体作为细胞能量工厂的功能的新知识。该项目还将从代表性不足的群体中招募参与者，以提高公平性。嵴是线粒体内膜的内陷，含有ADP氧化磷酸化所需的大部分生化酶。在胁迫下，嵴重构以可控的方式进行，这与氧化磷酸化的最大速率有关。本项目旨在确定这种相关性背后的因果机制。在Aim 1中，将利用从纯化线粒体收集的生物能量数据，通过计算机建模解释新的钙相关线粒体生理学。在Aim 2中，线粒体在特定条件下的低温电子断层图将用于在近纳米分辨率下量化嵴形态参数。在Aim 3中，将使用限制氧化磷酸化生化反应/扩散模型的3D空间模型来揭示调节能量代谢和嵴形态的生物物理机制。通过揭示线粒体结构/功能关系的机制，该项目将开辟新的科学探索途径，专注于改善全世界人民的健康和福祉。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Mitochondria are subcellular organelles that are essential for energy production in so-called higher organisms, like plants and animals, including humans. However, we do not fully understand how the makeup and structure of mitochondria determine their life-sustaining abilities. We do know that biochemical reactions in mitochondria are separated into compartments known as cristae, which become disrupted under stress. To understand the reasons for this disruption, this project will employ advanced microscopy to visualize mitochondrial structural details and molecular methods to mimic disrupted mitochondrial metabolism. The project will provide educational experiences to high school students and teachers and research experiences to undergraduate and graduate students, who will learn how theoretical concepts can be linked through experiments to produce new knowledge of how mitochondria function as the energy factories of cells. The project will also recruit participants from underrepresented groups to improve equity. Cristae are invaginations of the inner membrane of mitochondria that contain the bulk of the biochemical enzymes required for the oxidative phosphorylation of ADP. Under stress, cristae remodel in a controllable manner, which correlates with the maximum rate of oxidative phosphorylation. This project seeks to identify causal mechanisms behind this correlation. In Aim 1, novel calcium related mitochondrial physiology will be elucidated using bioenergetic data collected from purified mitochondria, interpreted via computer modeling. In Aim 2, cryo-electron tomograms of mitochondria in specific conditions will be used to quantify cristae morphology parameters at near-nanometer resolution. In Aim 3, 3D spatial models constraining a biochemical reaction/diffusion model of oxidative phosphorylation will be used to reveal the biophysical mechanisms regulating energy metabolism and cristae morphology. By uncovering the mechanisms underlying the structure/function relationship of mitochondria, this project will open new avenues of scientific inquiry focused on improving the health and well-being of people across the world.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.