Mitochondrial complex I bridges a connection between regulation of carbon flexibility and gastrointestinal commensalism in the human fungal pathogen Candida albicans.
Mitochondrial complex I bridges a connection between regulation of carbon flexibility and gastrointestinal commensalism in the human fungal pathogen Candida albicans.
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线粒体复合物 I 在人类真菌病原体白色念珠菌中架起了碳灵活性调节与胃肠道共生之间的联系
DOI：
10.1371/journal.ppat.1006414
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发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Huang X;Chen X;He Y;Yu X;Li S;Gao N;Niu L;Mao Y;Wang Y;Wu X;Wu W;Wu J;Zhou D;Zhan X;Chen C
白念珠菌是一种常见的酵母菌，经常引起人的机会性感染，在葡萄糖限制的宿主环境中有效地吸收替代碳源对于白色念珠菌的定植至关重要。白念珠菌通过机械进化来调节替代碳的同化作用，以促进真菌的生长和哺乳动物宿主的共生。然而，白念珠菌用来应对替代碳同化的这种高度适应性的机制还没有被清楚地理解。在这里，我们确定了白色念珠菌线粒体复合体I(CI)在调节甘露醇等替代碳源的同化中的新作用。我们的数据表明，在以甘露醇为碳源而不是葡萄糖等发酵糖的条件下，CI功能障碍通过缺失Nuo2亚基来降低NAD+水平，下调依赖NAD+的甘露醇脱氢酶活性，从而抑制菌丝生长和生物膜形成。甘露醇依赖的形态发生受ROS诱导的信号通路控制，该信号通路涉及Hog1激活和BRG1抑制。体内研究表明，NUO2Δ/Δ突变细胞在胃肠道的定植受到严重损害，这种缺陷可以通过高糖饮食来挽救。因此，我们的发现揭开了白色念珠菌调节碳灵活性和共生性的机制。替代的碳同化作用可能代表了共生真菌在寄主生态位成功定植中的一种适应性优势。
Efficient assimilation of alternative carbon sources in glucose-limited host niches is critical for colonization of Candida albicans, a commensal yeast that frequently causes opportunistic infection in human. C. albicans evolved mechanistically to regulate alternative carbon assimilation for the promotion of fungal growth and commensalism in mammalian hosts. However, this highly adaptive mechanism that C. albicans employs to cope with alternative carbon assimilation has yet to be clearly understood. Here we identified a novel role of C. albicans mitochondrial complex I (CI) in regulating assimilation of alternative carbon sources such as mannitol. Our data demonstrate that CI dysfunction by deleting the subunit Nuo2 decreases the level of NAD+, downregulates the NAD+-dependent mannitol dehydrogenase activity, and consequently inhibits hyphal growth and biofilm formation in conditions when the carbon source is mannitol, but not fermentative sugars like glucose. Mannitol-dependent morphogenesis is controlled by a ROS-induced signaling pathway involving Hog1 activation and Brg1 repression. In vivo studies show that nuo2Δ/Δ mutant cells are severely compromised in gastrointestinal colonization and the defect can be rescued by a glucose-rich diet. Thus, our findings unravel a mechanism by which C. albicans regulates carbon flexibility and commensalism. Alternative carbon assimilation might represent a fitness advantage for commensal fungi in successful colonization of host niches.