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.

项目总结/摘要 线粒体容纳所有生命构件的代谢，并且是细胞代谢的中心， 然而，对于代谢物如何穿过线粒体膜转运知之甚少; 对神经元细胞代谢的影响尚待探索。线粒体载体SLC 25家族 代表线粒体代谢物转运关键的最大蛋白质家族，其中大约 在53个人类SLC 25基因中，有20个基因的功能仍然未知。我们的总体研究计划是 通过鉴定内源性代谢物配体来表征线粒体代谢物转运， SLC 25转运蛋白。最近，我的实验室应用线粒体代谢组学来发现线粒体的作用。 线粒体转运蛋白SLC 25 A39在谷胱甘肽摄取中的特征不佳（由R 00支持）。在这里， 基于这一最新进展，我们建议将该策略扩展到其他SLC 25运输机， 细胞功能丧失和功能获得研究。作为一种独特和互补的方法，我们将 对SLC 25转运蛋白进行序列和结构分析， 代谢物摄取筛选，目的是表征配体识别机制。研究线粒体 我们将采用iPSC衍生的神经元作为体外模型，以分析iPSC对神经元代谢的影响。 SLC 25转运蛋白在线粒体和突触代谢上的损失。总之，我们对SLC 25的研究 转运蛋白将揭示线粒体代谢物转运的基础生物学，这是一个新兴的新领域 细胞代谢的前沿。我们在细胞代谢方面的专业知识，独特地应用最先进的，高- 分辨率质谱代谢组学基础生物化学和细胞生物学，是非常适合 研究方向。ESI-MIRA计划使我能够在蜂窝领域开展研究生涯 代谢以及进入神经细胞生物学的新研究领域。资金的灵活性 这一机制使这个雄心勃勃的项目能够系统地解码线粒体代谢物的运输。