A systems approach to decode mitochondrial metabolite transport

解码线粒体代谢物运输的系统方法

• 批准号: 10713145
• 负责人: Hongying Shen
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713145
• 关键词: Adopted; Area; Biochemistry; Biology; Brain Diseases; Cells; Cellular biology; Family; Functional disorder; Funding Mechanisms; Genes; Glutathione; Goals; Human; In Vitro; Induced pluripotent stem cell derived neurons; Laboratories; Life; Ligands; Mediating; Metabolism; Mitochondria; Molecular; Neurons; Organelles; Process; Protein Family; Proteins; Research; Resolution; Role; Structure; Synapses; System; career; flexibility; frontier; gain of function; human disease; in vitro Model; loss of function; metabolomics; mitochondrial membrane; mitochondrial metabolism; programs; uptake

Project Summary/Abstract Mitochondria house the metabolism of all building blocks of life and are central for cellular metabolism, however, how metabolites translocate across the mitochondrial membrane is poorly understood; and the impact on neuronal cellular metabolism is yet to be explored. The mitochondrial carrier SLC25 family represents the largest protein family critical for mitochondrial metabolite transport, in which approximately 20 out of the 53 human SLC25 genes remain of unknown function. Our overarching research program is to characterize mitochondrial metabolite transport by identifying the endogenous metabolite ligands for SLC25 transporters. Recently, my laboratory applied mitochondrial metabolomics to discover the role of a poorly characterized mitochondrial transporter SLC25A39 in glutathione uptake (supported by R00). Here, building upon this recent progress, we propose to expand the strategy to other SLC25 transporters using loss-of-function and gain-of-function study in cells. As a distinct and complementary approach, we will apply sequence and structure analysis towards SLC25 transporter to guide in vitro mitochondrial metabolite uptake screen with a goal to characterize ligand recognition mechanism. To study mitochondrial metabolism in neurons, we will adopt iPSC-derived neurons as an in vitro model to profile the impact of SLC25 transporters loss on mitochondrial and synaptic metabolism. Together, our study of SLC25 transporters would reveal fundamental biology in mitochondrial metabolite transport, an emerging new frontier in cellular metabolism. Our expertise in cellular metabolism, uniquely in applying state-of-art, high- resolution mass spec metabolomics to fundamental biochemistry and cell biology, is perfectly suited for the research direction. The ESI-MIRA program enables launching my research career in cellular metabolism as well as moving into a new research area in neuronal cell biology. The flexibility in the funding mechanism allows this ambitious project to systematically decode mitochondrial metabolite transport.

项目摘要/摘要 线粒体房屋的所有生命基础的代谢，对于细胞代谢而言是中心的， 然而，对线粒体膜的代谢产物如何易于理解。和 对神经元细胞代谢的影响尚待探讨。线粒体载体SLC25家族 代表了线粒体代谢物转运至关重要的最大蛋白质家族，其中大约 在53个人类SLC25基因中，有20个仍然是未知功能。我们的总体研究计划是 通过识别内源性代谢物配体的线粒体代谢产物转运来表征线粒体代谢产物的转运 SLC25转运蛋白。最近，我的实验室应用线粒体代谢组学发现了 谷胱甘肽摄取中的线粒体转运蛋白SLC25A39的特征不佳（由R00支撑）。这里， 在最近的进展之下，我们建议将策略扩展到其他SLC25运输商 细胞的功能丧失和功能收益研究。作为一种独特而互补的方法，我们将 将序列和结构分析应用于SLC25转运蛋白以指导体外线粒体 代谢物吸收屏幕的目标是表征配体识别机制。研究线粒体 神经元中的代谢，我们将采用IPSC衍生的神经元作为体外模型来介绍 SLC25线粒体和突触代谢的转运蛋白损失。一起，我们对SLC25的研究 转运蛋白会揭示线粒体代谢物运输中的基本生物学，这是一种新的新型生物学 细胞代谢的边界。我们在细胞代谢方面的专业知识，独特地应用了最先进的高级，高 解决基本生物化学和细胞生物学的分辨率质量代谢组学非常适合 研究方向。 ESI-MIRA计划使我的蜂窝研究生涯启动我的研究生涯 代谢以及进入神经元细胞生物学的新研究领域。资金的灵活性 机制使这个雄心勃勃的项目可以系统地解码线粒体代谢产物的运输。