Iron sensing is governed by mitochondrial, but not by cytosolic iron-sulfur cluster biogenesis in Aspergillus fumigatus
For optimal growth, microorganisms have to adapt their iron metabolism to the requirements of their ecological niche to avoid iron shortage as well as iron toxicity. Therefore, mechanisms have been evolved to tightly regulate iron uptake, consumption and detoxification, respectively, which depend on sensing the cellular iron status. In the facultative anaerobic yeast Saccharomyces cerevisiae, iron sensing has been shown to depend on mitochondrial (MIA) but not cytosolic iron-sulfur cluster assembly (CIA), while in mammals the cellular iron state is sensed via cytosolically synthesized iron-sulfur clusters. To address the question how the obligatory aerobic mold Aspergillus fumigatus senses the cellular iron state, mutant strains allowing down-regulation of MIA and CIA were generated. These studies revealed that: (i) Af‑Nfs1 (Afu3g14240) and Af‑Nbp35 (Afu2g15960), which are required for MIA and CIA, respectively, are essential for growth; (ii) inactivation of the Frataxin homolog Af‑FxnA (Afu4g10510), which is involved in MIA, is not lethal, but results in a severe growth defect; (iii) a decrease in MIA (Af-Nfs1 depletion, Af‑FxnA-deficiency) but not CIA (Af-Nbp35 depletion) results in an iron starvation response accompanied by increased iron toxicity; and, likewise, (iv) a decrease in mitochondrial iron import results in an iron starvation response. Taken together, these data underline that iron sensing in A. fumigatus depends on the mitochondrial, but not the cytosolic iron-sulfur cluster machinery. Moreover, depletion of the glutathione pool caused an iron starvation response underlining a crucial role of glutathione in iron sensing in A. fumigatus.