Cryptococcus neoformans Mar1 function links mitochondrial metabolism, oxidative stress, and antifungal tolerance

Together, these studies support an emerging model in which the metabolic activity of microbial cells directs cell physiological changes to allow persistence in the face of antimicrobial and host stress.

Here, we use comparative transcriptomics, protein localization, and phenotypic analysis of a mar1D loss-of-function mutant strain to further define the role of C. neoformans Mar1 in stress response and antifungal resistance.

We demonstrate that C. neoformans Mar1 is highly enriched in mitochondria. Furthermore, a mar1Δ mutant strain is impaired in growth in the presence of select electron transport chain inhibitors, has altered ATP homeostasis, and promotes proper mitochondrial morphogenesis. Pharmacological inhibition of complex IV of the electron transport chain in wild-type cells promotes similar cell wall changes as the mar1Δ mutant strain, supporting prior associations between mitochondrial function and cell wall homeostasis. Although Mar1 is not required for general susceptibility to the azole antifungals, the mar1Δ mutant strain displays increased tolerance to fluconazole that correlates with repressed mitochondrial metabolic activity.