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Feldberg Prize Lecture: Biogenesis of iron-sulfur proteins in eukaryotes

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Iron-sulfur (Fe/S) clusters are simple and evolutionary ancient inorganic cofactors of proteins with a function in catalysis, electron transfer and regulation. The molecular basis of Fe/S cluster synthesis and its assembly into apoproteins in a living cell has been subject to intense research activities over the past years (see Reviews). Biogenesis is accomplished by three complex proteinaceous machineries (Figure). Mitochondrial Fe/S proteins require the iron-sulfur cluster (ISC) assembly machinery which was inherited from bacteria during evolution. Cytosolic and nuclear Fe/S protein assembly also depends on the function of this machinery, yet additionally requires the mitochondrial ISC export apparatus and the cytosolic iron-sulfur protein assembly (CIA) machinery. General principles seem to underlie the assembly processes in both the mitochondria and the cytosol/nucleus, even though the ISC and CIA components do not show any similarity (Lill, 2009). The components of all three systems (more than 25 proteins) are highly conserved from yeast to man suggesting similar mechanisms of Fe/S protein assembly in all eukaryotes. Defects in Fe/S protein biogenesis result in the loss of cell viability. This is due to essential cytosolic and nuclear Fe/S proteins involved in DNA replication and repair as well as ribosome assembly and function. The dependence of their assembly on mitochondria explains why mitochondria (or mitochondria-derived organelles such as mitosomes and hydrogenosomes) are indispensable in virtually all eukaryotic cells, and show the crucial function of mitochondria in basic processes of DNA and RNA metabolism. Fe/S protein biogenesis is of importance for human disease in that more than ten diseases are associated with ISC , CIA or Fe/S protein defects. For instance, depletion of the ISC assembly component frataxin leads to the neurodegenerative disease Friedreich’s ataxia, and a defect in the ISC export protein ABCB7 is associated with X-linked sideroblastic anemia and ataxia (XLSA/A). Fe/S protein defects in nuclear DNA replication and repair proteins link Fe/S protein biogenesis to numerous diseases including various forms of cancer.

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