Systems biology approaches to study mammalian mitochondrial metabolism

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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.