A Putative Mitochondrial Iron Transporter MrsA in Aspergillus fumigatus Plays Important Roles in Azole-, Oxidative Stress Responses and Virulence.
A Putative Mitochondrial Iron Transporter MrsA in Aspergillus fumigatus Plays Important Roles in Azole-, Oxidative Stress Responses and Virulence.
复制标题
烟曲霉中假定的线粒体铁转运蛋白 MrsA 在唑、氧化应激反应和毒力中发挥重要作用
DOI：
10.3389/fmicb.2016.00716
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发表时间：
2016
影响因子：
5.2
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Long N;Xu X;Qian H;Zhang S;Lu L
铁是一种必需的营养素和酶辅助因子，需要广泛的细胞过程，特别是线粒体的功能。对于条件真菌病原体烟曲霉，在感染过程中获得铁的能力是生长和毒力所必需的。然而，关于线粒体如何参与铁调节的知识仍然有限。在这里，我们证明了一种线粒体铁转运蛋白MrsA，酵母Mrs4p的同源物，对于烟曲霉适应铁限制或铁过剩的条件至关重要。mrsA的缺失导致铁稳态的破坏和sreA表达的降低，导致活化的还原性铁同化（RIA）和铁载体介导的铁获取（SIA）。此外，mrsA的缺失诱导了对唑和氧化应激的超敏感。结合抗氧化试剂l -抗坏血酸对mrsa缺陷表型的拯救，对ΔmrsA细胞ROS含量的测定表明，ΔmrsA对唑伊曲康唑和氧化应激敏感性的增加主要是ROS异常积累的结果。此外，位点定向突变实验证实，MrsA中与铁转运相关的三个保守组氨酸残基对氧化和唑胁迫的反应是必需的。重要的是，ΔmrsA在免疫功能低下的曲霉病小鼠模型中引起毒力的显著衰减。总之，我们的研究结果表明，假定的线粒体铁转运体MrsA通过调节烟曲霉细胞铁的平衡，在唑和氧化应激反应和毒力中发挥重要作用。
Iron is an essential nutrient and enzyme co-factor required for a wide range of cellular processes, especially for the function of mitochondria. For the opportunistic fungal pathogen Aspergillus fumigatus, the ability to obtain iron is required for growth and virulence during the infection process. However, knowledge of how mitochondria are involved in iron regulation is still limited. Here, we show that a mitochondrial iron transporter, MrsA, a homolog of yeast Mrs4p, is critical for adaptation to iron-limited or iron-excess conditions in A. fumigatus. Deletion of mrsA leads to disruption of iron homeostasis with a decreased sreA expression, resulted in activated reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA). Furthermore, deletion of mrsA induces hypersusceptibility to azole and oxidative stresses. An assay for cellular ROS content in ΔmrsA combined with rescue from the mrsA-defective phenotype by the antioxidant reagent L-ascorbic acid indicates that the increased sensitivity of ΔmrsA to the azole itraconazole and to oxidative stress is mainly the result of abnormal ROS accumulation. Moreover, site-directed mutation experiments verified that three conserved histidine residues related to iron transport in MrsA are required for responses to oxidative and azole stresses. Importantly, ΔmrsA causes significant attenuation of virulence in an immunocompromised murine model of aspergillosis. Collectively, our results show that the putative mitochondrial iron transporter MrsA plays important roles in azole- and oxidative-stress responses and virulence by regulating the balance of cellular iron in A. fumigatus.