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AmcA-a putative mitochondrial ornithine transporter supporting fungal siderophore biosynthesis
Lukas Schafferer1, Nicola Beckmann1, Ulrike Binder2
1Division of Molecular Biology/Biocenter, Medical University Innsbruck Innsbruck, Austria.
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.
Insights
The mitochondrial transporter AmcA is crucial for Aspergillus fumigatus siderophore biosynthesis by regulating ornithine levels. Its deficiency impacts fungal growth and susceptibility to inhibitors, but not virulence in a host model.
Area of Science:
- Mycology
- Molecular Biology
- Biochemistry
Background:
- Iron is essential for cellular processes, and Aspergillus fumigatus uses siderophores for iron uptake.
- Siderophore biosynthesis (SB) requires ornithine, which is produced in mitochondria and cytosol.
- The role of mitochondrial transporters in fungal SB and iron metabolism is not fully understood.
Purpose of the Study:
- To investigate the function of the putative mitochondrial transporter AmcA in Aspergillus fumigatus siderophore biosynthesis.
- To determine the impact of AmcA deficiency on cellular ornithine and arginine levels.
- To assess the role of AmcA in fungal growth, polyamine metabolism, and virulence.
Main Methods:
- Gene deletion to create AmcA-deficient A. fumigatus.
- Measurement of cellular ornithine, arginine, and polyamine content.
- Analysis of siderophore production and gene expression via Northern blot.
- Assessment of fungal growth rates under various nutrient conditions and iron availability.
- Evaluation of virulence in the Galleria mellonella infection model.
Main Results:
- AmcA-deficiency decreased cellular ornithine and arginine, and reduced siderophore production when glutamine was the sole nitrogen source.
- Siderophore biosynthesis gene expression was not directly responsive to cellular ornithine levels.
- AmcA deficiency mildly decreased polyamine content but increased susceptibility to eflornithine.
- AmcA-deficiency impaired fungal growth, particularly on ornithine during iron starvation.
- AmcA-deficient A. fumigatus showed no significant difference in virulence in the Galleria mellonella model.
Conclusions:
- The mitochondrial transporter AmcA plays a significant role in regulating ornithine levels, impacting siderophore biosynthesis and fungal fitness in Aspergillus fumigatus.
- AmcA appears to be involved in mitochondrial ornithine import, influencing cellular metabolism and growth.
- Despite its role in iron acquisition, AmcA deficiency did not attenuate fungal virulence in the Galleria mellonella model, likely due to compensatory mechanisms.
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