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

职业：阐明与能量代谢和线粒体超微结构相关的因果关系

• 批准号: 2237117
• 负责人: Jason Bazil
• 金额: $ 88.8万
• 依托单位: Michigan State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2237117&HistoricalAwards=false
• 关键词: CAREER; Elucidating; Causal; Link; Associated

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.

线粒体是亚细胞细胞器，对于所谓的高等生物（包括人类）等所谓的高等生物中的能量生产至关重要。但是，我们不完全了解线粒体的构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称为cristae的隔室，在压力下被破坏。为了理解这种破坏的原因，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，以模仿干扰线粒体代谢。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，以对线粒体如何作为细胞的能源工厂产生新知识。该项目还将招募来自代表性不足的群体的参与者以提高公平性。 cristae是线粒体内膜的起伏，其中包含ADP氧化磷酸化所需的大部分生化酶。在压力下，Cristae重塑以可控的方式重塑，这与最大的氧化磷酸化速率相关。该项目旨在确定这种相关性背后的因果机制。在AIM 1中，将使用从纯化的线粒体收集的生物能数据来阐明与钙相关的新型线粒体生理，这是通过计算机建模来解释的。在AIM 2中，在特定条件下，线粒体的冷冻电子断层图将用于量化近纳米分辨率下的Cristae形态参数。在AIM 3中，约束氧化磷酸化生化反应/扩散模型的3D空间模型将用于揭示调节能量代谢和CRISTAE形态的生物物理机制。通过揭示线粒体结构/功能关系的基础机制，该项目将开放科学探究的新途径，重点是改善全球人的健康和福祉。该奖项反映了NSF的法定任务，并通过使用该基金会的智力物品和广泛的影响来评估NSF的法定任务，并被认为是值得通过评估的支持。