The role of mitochondria for molybdenum cofactor biosynthesis

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It is the aim of this project to study the role of mitochondria for molybdenum cofactor (Moco) biosynthesis and molybdenum-enzyme activity. Until recently it was generally believed that Moco-biosynthesis and molybdenum-enzyme formation exclusively proceed in the cytoplasm. Our preliminary work, however, has shown that a crosstalk exists between Mocosynthesis and availability of [Fe-S]-clusters from mitochondria. The ABC-type transporter ATM3 in the inner membrane of mitochondria is known to export [Fe-S] into the cytoplasm. The knock-out of ATM3, however, impairs not only [Fe-S] export but unexpectedly leads to the accummulation of precursorZ (= first intermediate in Moco-biosynthesis) while the amounts of the subsequent cytoplasmic reaction intermediates of Moco-biosynthesis are severely lowered. This might indicate that the first step of Moco-biosynthesis takes place in mitochondria. - In this project we want to unveil whether precursorZ really is generated inside the mitochondria, and if so, whether the enzyme complex that catalyzes the conversion of precursorZ to molybdopterin, MPT-synthase, is associated with the outer membrane of mitochondria. We want to delineate the role played by the ABC-type transporter ATM3 for Moco-biosynthesis. Further we want to clarify the importance of mitochondria for the maturation of molybdenum-enzymes and provide molecular detail on the cross-talk of Mocoand [Fe-S]-biosynthesis. The combination of different approaches will allow us to get a detailed insight into how mitochondria contribute to Moco-biosynthesis and to the formation of molybdenum-enzymes in the cytoplasm.