Studien zur funktionellen Charakterisierung der humanen und murinen mARC-Proteine

The mitochondrial amidoxime-reducing component mARC was identified in 2006 as a hitherto unknown molybdenum-containing protein located in the outer mitochondrial membrane. All annotated mammalian genomes contain two MTARC genes: MTARC1 and MTARC2, which encode the two proteins mARC1 and mARC2. These enzymes exert N‑reductive activity towards a variety of N-oxygenated substrates together with the two mitochondrial electron carrier proteins cytochrome b5 B and cytochrome b5 reductase isoform 3.

In this thesis, different biological assays were established in order to characterize the paralogous and orthologous human and murine proteins in one hand, and to further establish the physiological function of mARC on the other.

Studies in mARC1- and mARC2-deficient mice show a key role of mARC in reductive metabolism. Using CRISPR/Cas9, the (to date) first stable knockout of a MTARC gene was generated in human cells. In cellulo studies showed a significantly reduced N-reductive activity of mARC1-deficient cells. In addition, mARC1 was found to be involved in detoxyfying metabolism through, inter alia, the reduction of 6-N-hydroxyaminopurine. Murine in vivo studies revealed MTARC2-KO-mediated resistance to high-fat-induced obesity and micro-vesicular steatosis. Blood analyses confirmed a hepatoprotective effect through reduced liver enzyme levels and showed reduced total cholesterol, glucose and triglyceride levels.

In conclusion, this work confirms a clear link between mARC and lipid metabolism. In addition, the MTARC-KO mouse model is validated as a powerful tool for predicting mARC‑mediated drug metabolism.


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