Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis.
Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis.
复制标题
白色念珠菌线粒体复合物 I 的真菌特异性亚基驱动多种细胞功能，包括细胞壁合成。
DOI：
10.1111/cmi.12438
复制
发表时间：
2015-09
影响因子：
3.4
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
She X;Khamooshi K;Gao Y;Shen Y;Lv Y;Calderone R;Fonzi W;Liu W;Li D
我们发表的研究集中在Goa 1 p的作用，Goa 1 p是白色念珠菌线粒体复合物I（CI）的明显调节因子。缺乏Goa 1 p影响最佳细胞生长、CI活性和毒力。真核CI由14个α-变形菌亚基蛋白的核心和可变数量的额外亚基蛋白组成。在后一组蛋白中，一种（NUZM）是真菌特异性的，第二种（NUXM）在真菌、藻类和植物中发现，但不是哺乳动物Cl亚基蛋白。我们确定了C.白色念珠菌在此，我们验证了这两个亚基蛋白作为NADH：泛醌氧化还原酶（NUO）和注释他们的基因功能。为了实现这些目标，我们比较了野生型和基因重组菌株的无效突变体。基因NUO 1（19.6607）和NUO 2（19.287）的遗传突变体，毫不奇怪，各自具有减少的耗氧量、降低的线粒体氧化还原电位、降低的CI活性、增加的活性氧化剂物质（ROS）和体外时间老化的减少。任何一个基因的缺失都会导致CI的解体。这两种突变体的转录谱表明碳代谢基因的显著下调，以及可能发生以补偿CI活性损失的神经元相关基因家族的上调。两种突变体的分析也证明了细胞壁β-甘露糖基化的损失，但不是在保守的Cl亚基（ndh 51 Δ）中。分析数据可以指示由Nuo 1 p和Nuo 2 p的酶活性驱动的特定功能。重要的是，每种突变体在与其减少的组织定殖相关的鼠血源性侵袭性念珠菌病模型中也是无毒的。基于它们的真菌特异性和毒力作用，我们建议两者作为抗真菌药物发现的药物靶点。
Our published research has focused upon the role of Goa1p, an apparent regulator of the Candida albicans mitochondrial complex I (CI). Lack of Goa1p effects optimum cell growth, CI activity, and virulence. Eukaryotic CI is composed of a core of 14 alpha-proteobacterial subunit proteins and a variable number of supernumerary subunit proteins. Of the latter group of proteins, one (NUZM) is fungal-specific, and a second (NUXM) is found in fungi, algae and plants but is not a mammalian CI subunit protein. We have established that NUXM is orf19.6607 and NUZM is orf19.287 in C. albicans. Herein, we validate both subunit proteins as NADH:ubiquinone oxidoreductases (NUO) and annotate their gene functions. To accomplish these objectives, we compared null mutants of each with WT and gene-reconstituted strains. Genetic mutants of genes NUO1 (19.6607) and NUO2 (19.287), not surprisingly, each had reduced oxygen consumption, decreased mitochondrial redox potential, decreased CI activity, increased reactive oxidant species (ROS), and a decrease in chronological aging in vitro. Loss of either gene results in a disassembly of CI. Transcriptional profiling of both mutants indicated significant down regulation of genes of carbon metabolism, as well as upregulation of mitochondrial-associated gene families which may occur to compensate for the loss of CI activity. Profiling of both mutants also demonstrated a loss of cell wall β-mannosylation but not in a conserved CI subunit (ndh51Δ). The profiling data may indicate specific functions driven by the enzymatic activity of Nuo1p and Nuo2p. Of importance, each mutant is also avirulent in a murine blood-borne, invasive model of candidiasis associated with their reduced colonization of tissues. Based upon their fungal-specificity and roles in virulence, we suggest both as drug targets for antifungal drug discovery.