A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling

The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. [Display omitted] •The mitochondrial fission inhibitor mdivi-1 represses Candida hyphal morphogenesis•Inhibition of hyphal growth by mdivi-1 is independent of its putative target, Dnm1•Mdivi-1 reprograms metabolic gene expression and reduces endogenous NO levels•Endogenous NO signaling controls hyphal morphogenesis in Candida Hyphal morphogenesis contributes to virulence of the human fungal pathogen Candida albicans. Koch et al. show that mdivi-1, a putative inhibitor of mitochondrial division, represses hyphal growth of Candida and implicate regulation of endogenous nitric oxide levels in the mechanism of action of mdivi-1 and the regulation of hyphal morphogenesis.