The Mcu1 mitochondrial protein coordinates TCA cycle enzymes to modulate phenotypic switching and commensalism in Candida albicans.

Candida albicans is a common resident of humans that colonizes multiple sites in the human body, such as the gut, in healthy individuals. In immunocompromised hosts, however, it can switch to a pathogenic state and cause infections. The molecular mechanisms underlying this commensal-pathogenic transition have not been fully elucidated. Here, we demonstrate that the mitochondrial protein Mcu1, which is required for utilization of multiple carbon sources, plays a crucial role in N-acetylglucosamine (GlcNAc)-induced phenotypic switching and gut commensalism in C. albicans. Disruption of Mcu1 or key TCA cycle enzymes impaired GlcNAc utilization, blocked white-to-opaque switching under in vitro culture conditions, and reduced gut colonization in a murine model. Mechanistically, Mcu1 sustains respiratory metabolism by regulating key oxidoreductases, while also promoting gut commensalism by enabling in vivo activation of the master regulator Wor1. Collectively, our findings reveal that Mcu1 and key TCA cycle enzymes play an essential role in phenotypic switching and cooperatively regulate the commensal-pathogenic transition in C. albicans.