We are interested in the cellular biology of the transition metal iron - an essential trace element for virtually all organisms. Although iron is the second most abundant metal in the Earth’s crust, its bioavailability is low, since iron is rapidly oxidized in an aerobic environment to the ferric form, Fe(III), which has a poor solubility in water at neutral pH. For microbial pathogens, acquisition of host iron is frequently crucial for virulence and, mutations in genes involved in iron acquisition or iron utilization are frequently associated with loss of pathogenicity. Accordingly, mammals react to microbial infections by inducing iron-withholding defense systems, in order to deprive pathogens of essential iron in body fluids. On the other hand, high intracellular iron levels are a source of reactive oxygen species and thus toxic. To achieve appropriate cellular iron levels and to avoid iron-loading, cells have developed sophisticated systems for assuring a balanced cellular iron homeostasis. A tightly regulated iron metabolism is essential, and disruption or de-regulation of iron-related molecules can have significant health consequences.

Our work focusses on three main aspects of celluar iron metabolism:

In eukaryotes, mitochondria are the major iron-utilizing cell organelles as they play a central role in the maturation of all cellular iron-sulphur (Fe/S) proteins and are the unique site for heme synthesis. The biogenesis of Fe/S proteins by the mitochondrial iron-sulphur cluster assembly (ISC) is an essential task of mitochondria. Using yeast genetics, protein biochemistry and protein spectroscopic techniques, we focus on unravelling the de novo synthesis of Fe/S clusters by the early ISC assembly system and the transfer and insertion of these pre-assembled clusters into recipient apo-proteins by late ISC factors.

We study two aspects of the interplay between these important cellular systems. First, Fe/S proteins and their assembly factors are sensitive to oxidative damage and thus require protection by the cellular thioredoxin and glutaredoxin systems. Moreover, the biogenesis of cellular Fe/S proteins involves two monothiol glutaredoxins (Grx). The mitochondrial monothiol Grx5, plays a central role in the transfer and insertion of Fe/S clusters into mitochondrial Fe/S apo-proteins. The cytosolic monothiol Grx4 plays a cental role in cytosolic iron trafficking to cell organelles, including mitochondria, and several iron-dependent proteins including those of the cytosolic iron-sulphur protein assembly (CIA) systems.

Micro-organism adapt to conditions of iron deprivation by both the induction of genes involved in iron uptake and the parallel down-regulation of components involved in iron storage and utilization. This minimizing of iron-consuming processes during iron limitation is an attempt to liberate and spare iron for more essential tasks. In higher eukaryotes and fungi alike, defects in the mitochondrial ISC systems trigger a substantial remodelling of the cellular iron metabolism that is very similar to that induced upon iron deprivation. Using S. cerevisiae as a model, we study the cross-talk between the cellular Fe/S assembly systems and the regulation iron-responsive transcription factors. The regulation of these transcription factors further essentially involves the cytosolic Grx4.

For an overview see:

1. Freibert, S. A. et al. Biochemical Reconstitution and Spectroscopic Analysis of Iron-Sulfur Proteins. Methods Enzymol 599, 197–226 (2018).

2. Mühlenhoff, U. et al. Compartmentalization of iron between mitochondria and the cytosol and its regulation. Eur J Cell Biol 94, 292–308 (2015).