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

线粒体是亚细胞细胞器，对所谓的高等生物，如植物和动物，包括人类，产生能量是必不可少的。然而，我们并不完全了解线粒体的组成和结构如何决定其维持生命的能力。我们确实知道，线粒体中的生化反应被分成几个被称为脊的空间，在压力下会被破坏。为了了解这种中断的原因，该项目将使用先进的显微镜来可视化线粒体结构细节，并使用分子方法来模拟中断的线粒体代谢。该项目将为高中生和教师提供教育经验，向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，以产生关于线粒体如何作为细胞能量工厂的新知识。该项目还将从代表性不足的群体中招募参与者，以改善公平。冠状突起是线粒体内膜的内陷，含有ADP氧化磷酸化所需的大量生化酶。在应激状态下，脊骨以一种可控的方式重塑，这与氧化磷酸化的最大速率有关。这个项目试图找出这种关联背后的因果机制。在目标1中，将使用从纯化的线粒体收集的生物能量数据来阐明与钙相关的新的线粒体生理学，并通过计算机模拟进行解释。在目标2中，将使用特定条件下线粒体的冷冻电子断层图像来在近纳米分辨率下量化晶体的形态参数。在目标3中，将使用3D空间模型来约束氧化磷酸化的生化反应/扩散模型，以揭示调节能量代谢和眉骨形态的生物物理机制。通过揭示线粒体结构/功能关系的潜在机制，该项目将开辟新的科学研究途径，专注于改善世界各地人们的健康和福祉。该奖项反映了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。

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.