AUTHOR=Telzrow Calla L. , Esher Righi Shannon , Cathey Jackson M. , Granek Joshua A. , Alspaugh J. Andrew 

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

JOURNAL=Frontiers in Physiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1150272

DOI=10.3389/fphys.2023.1150272

ISSN=1664-042X

ABSTRACT=<p><bold>Introduction:</bold> Microbial pathogens undergo significant physiological changes during interactions with the infected host, including alterations in metabolism and cell architecture. The <italic>Cryptococcus neoformans</italic> Mar1 protein is required for the proper ordering of the fungal cell wall in response to host-relevant stresses. However, the precise mechanism by which this <italic>Cryptococcus</italic>-specific protein regulates cell wall homeostasis was not defined.</p><p><bold>Methods:</bold> Here, we use comparative transcriptomics, protein localization, and phenotypic analysis of a <italic>mar1D</italic> loss-of-function mutant strain to further define the role of <italic>C. neoformans</italic> Mar1 in stress response and antifungal resistance.</p><p><bold>Results:</bold> We demonstrate that <italic>C. neoformans</italic> Mar1 is highly enriched in mitochondria. Furthermore, a <italic>mar1</italic>Δ 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 <italic>mar1</italic>Δ 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 <italic>mar1</italic>Δ mutant strain displays increased tolerance to fluconazole that correlates with repressed mitochondrial metabolic activity.</p><p><bold>Discussion:</bold> 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.</p>