Systems biology approaches to study mammalian mitochondrial metabolism

研究哺乳动物线粒体代谢的系统生物学方法

• 批准号: 314568895
• 负责人: Professorin Dr. Thekla Cordes
• 金额: --
• 依托单位: Salk Institute for Biological Studies
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314568895?language=en
• 关键词: Systems; biology; approaches; study; mammalian

Mitochondria are the powerhouses of all eukaryotic cells important for energy generation and respiration but also for amino acid catabolism and biosynthesis. Although many diseases are associated with dysfunctional mitochondrial metabolism surprisingly little is known about the import of amino acids and other molecules into the mitochondrial matrix. As such, many mitochondrial carriers remain unannotated, especially members of the solute carrier family 25 (SLC25). Alterations in SLC25 protein activity are associated with various metabolic dysfunctions and diseases. Identifying and characterizing SLC25 transporter function will enable me to impact human health in a number of ways. For example, one critical metabolic pathway in mitochondria is the early step of heme biosynthesis which utilizes the amino acid glycine for aminolevulinate synthesis. Since mutations of the mitochondrial carrier SLC25A38 results in impaired heme biosynthesis and formation of congenital sideroblastic anemia, this carrier may play a role for glycine transport into mitochondria. However, to date, the functional role of this mitochondrial carrier SLC25A38 in mitochondrial amino acid transport has not yet been discovered.The proposed research aims to functionally characterize unknown mitochondrial carriers associated with metabolic dysfunctions in mitochondria. To this end, I will apply cellular engineering, mass spectrometry, and metabolomics approaches with a focus on stable isotope tracing to study mammalian mitochondrial metabolism upon modulation of mitochondrial carrier activity. I will further assess mitochondrial dysfunction by measuring mitochondrial respiration. To shed light on glycine transport, I will initially focus on the carrier associated with heme biosynthesis, especially SLC25A38. Finally, all developed methods will be applied to characterize other unknown mitochondrial carriers in a discovery-based approach. Understanding amino acid transport into mitochondria can identify mitochondrial dysfunctional metabolism and disease formation. With this proposed research project I will gain valuable skills to dissect transporter function in great detail and discover and annotate unknown mitochondrial carriers. With this knowledge, I intend to shed light on the role of mitochondrial dysfunction in human health and disease. This DFG fellowship provides an important opportunity to guide my career as independent researcher. It will enhance my academic profile and qualify me for a career in my own academic research group which I intend to establish in Germany.

线粒体是所有真核细胞的发电站，对于能量产生和呼吸以及氨基酸催化和生物合成都很重要。虽然许多疾病与线粒体代谢功能障碍有关，但令人惊讶的是，对氨基酸和其他分子进入线粒体基质的情况知之甚少。因此，许多线粒体载体仍然未注释，特别是溶质载体家族25（SLC25）的成员。SLC25蛋白活性的改变与各种代谢功能障碍和疾病相关。确定和表征SLC25转运蛋白功能将使我能够以多种方式影响人类健康。例如，线粒体中的一个关键代谢途径是血红素生物合成的早期步骤，其利用氨基酸甘氨酸进行氨基乙酰丙酸合成。由于线粒体载体SLC25A38的突变导致血红素生物合成受损和先天性铁粒幼细胞性贫血的形成，该载体可能在甘氨酸转运到线粒体中起作用。然而，迄今为止，这种线粒体载体SLC25A38在线粒体氨基酸转运中的功能作用尚未被发现。拟议的研究旨在功能上表征与线粒体代谢功能障碍相关的未知线粒体载体。为此，我将应用细胞工程，质谱和代谢组学方法，重点是稳定同位素示踪研究哺乳动物线粒体代谢后，线粒体载体活性的调制。我将通过测量线粒体呼吸进一步评估线粒体功能障碍。为了阐明甘氨酸转运，我将首先关注与血红素生物合成相关的载体，特别是SLC25A38。最后，所有开发的方法将被应用到其他未知的线粒体载体的特征在一个发现为基础的方法。了解氨基酸转运到线粒体中可以识别线粒体代谢功能障碍和疾病形成。通过这个研究项目，我将获得宝贵的技能，详细剖析转运蛋白的功能，并发现和注释未知的线粒体载体。有了这些知识，我打算阐明线粒体功能障碍在人类健康和疾病中的作用。这个DFG奖学金提供了一个重要的机会，指导我的职业生涯作为独立的研究人员。这将提高我的学术形象，并使我有资格在我打算在德国建立的自己的学术研究小组中工作。