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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., Author summary Most fermentative sugars like glucose, although routinely used in laboratory cell culture medium, are in fact only present at very low levels and even absent in many host niches. Therefore, assimilation of alternative nutrients is essential for the survival, proliferation and infection of most clinically important microbial pathogens like C. albicans in their hosts. In this study, we show that mitochondrial complex I (CI) is indispensable for proper hyphal growth and biofilm formation of C. albicans cells when mannitol, but not fermentative sugars like glucose or mannose, is used as the sole carbon source. We also find that a specific signaling pathway that senses and responds to the alternative carbon source incorporates input from mitochondrially-derived molecules like reactive oxygen species (ROS) to influence activation of the Hog1 MAPK and expression of the biofilm-regulator Brg1. Our findings further demonstrate that CI dysfunction confers a severe defect of C. albicans in gastrointestinal colonization and changing the diet with glucose is able to significantly rescue the commensal defect. Our study suggests that C. albicans has a unique regulatory system to sense and utilize the alternative carbon sources abundant in the GI tract and to promote commensalism. Significantly, CI activity appears to play a vital role in this highly adaptive system to regulate commensalism, in addition to its well-characterized role in virulence.