Mitochondrial complex I bridges a connection between regulation of carbon flexibility and gastrointestinal commensalism in the human fungal pathogen Candida albicans

Abstract

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.

Genome-Scale Metabolic Model of the Human Pathogen Candida albicans: A Promising Platform for Drug Target Prediction

“…The results confirmed the model’s prediction regarding the utilization of cellobiose and D-Ribose ( Figure 3 ), suggesting that the reference C. albicans strain has higher metabolic capabilities, when compared to other strains. The model’s prediction failed only for mannitol that, according to the model, cannot be used as sole carbon source by C. albicans , contradicting experimental evidence gathered for the C. albicans SC5314 strain [ 61 , 62 ] ( Figure 3 ). It was not possible to identify the source of this problem in the built model.…”

The HOG MAPK pathway in Candida albicans: more than an osmosensing pathway

“…Another explanation could invoke the fact that these structures are formed under low oxygen concentrations and absence of light, suggesting a role for oxidative stress in this process. Recently, a role for mitochondrial complex I has been demonstrated in gastrointestinal commensalism (Huang et al 2017). The authors also demonstrate that mannitoldependent morphogenesis is controlled by an oxidative stress signaling pathway that requires Hog1 and Brg1 repression.…”

A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

“…Snf5 subunit of the SWI/SNF chromatin remodelling complex provides a nexus for integrating oxygen status to the carbon metabolic machinery and fungal fitness. As hypoxia is the predominant condition inside the host and since C. albicans utilizes different alternative carbon sources when persisting as a commensal [69] or infecting its host [70,71], SWI/SNF represents thus an attractive target for antifungal therapy.…”