Abstract
Iron is an essential nutrient required for a wide range of cellular processes. The opportunistic fungal pathogen Aspergillus fumigatus employs low-molecular mass iron-specific chelators, termed siderophores, for uptake, storage and intracellular iron distribution, which play a crucial role in the pathogenicity of this fungus. Siderophore biosynthesis (SB) depends on coordination with the supply of its precursor ornithine, produced mitochondrially from glutamate or cytosolically via hydrolysis of arginine. In this study, we demonstrate a role of the putative mitochondrial transporter AmcA (AFUA_8G02760) in SB of A. fumigatus. Consistent with a role in cellular ornithine handling, AmcA-deficiency resulted in decreased cellular ornithine and arginine contents as well as decreased siderophore production on medium containing glutamine as the sole nitrogen source. In support, arginine and ornithine as nitrogen sources did not impact SB due to cytosolic ornithine availability. As revealed by Northern blot analysis, transcript levels of siderophore biosynthetic genes were unresponsive to the cellular ornithine level. In contrast to siderophore production, AmcA deficiency did only mildly decrease the cellular polyamine content, demonstrating cellular prioritization of ornithine use. Nevertheless, AmcA-deficiency increased the susceptibility of A. fumigatus to the polyamine biosynthesis inhibitor eflornithine, most likely due to the decreased ornithine pool. AmcA-deficiency decreased the growth rate particularly on ornithine as the sole nitrogen source during iron starvation and sufficiency, indicating an additional role in the metabolism and fitness of A. fumigatus, possibly in mitochondrial ornithine import. In the Galleria mellonella infection model, AmcA-deficiency did not affect virulence of A. fumigatus, most likely due to the residual siderophore production and arginine availability in this host niche.
Highlights
Iron is an essential nutrient for virtually every organism known to mankind
After having observed decreased ornithine, in addition to decreased siderophore levels under glutamine supplementation, we considered it worthwhile to have a closer look at polyamine levels in the amcA mutant, as ornithine is the precursor for biosynthesis of siderophores, and polyamines
Despite the lack of direct prove, several lines of evidence indicate a function of AmcA in the supply of the precursor ornithine via mitochondrial ornithine export: (i) the
Summary
Iron is an essential nutrient for virtually every organism known to mankind. Its ability to adopt one of two ionic forms, reduced ferrous (Fe2+) or oxidized ferric (Fe3+) iron, makes it the major redox metal in cells. Abundant in the earth’s crust, its bioavailability is very low. The oxidized form, or more accurately oxyhydroxide colloid particles, is found in aerobic environments and shows a solubility below 10−9 M at neutral pH, which is insufficient to sustain vital. Apart from its crucial role in metabolism, including respiration, oxidative stress detoxification as well as synthesis of amino acids, lipids and desoxyribonucleic acid, iron is able to generate toxic reactive species if accumulated excessively (Halliwell and Gutteridge, 1984). Organisms have developed fine-tuned regulatory mechanisms regarding uptake, storage and consumption of iron
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