Qdr3 Coordinates Cellular Homeostasis, Mitochondrial Remodeling, and Virulence in Candidozyma auris (Candida auris)

Highlights

• Qdr3 coordinates cellular homeostasis in C. auris.

• qdr3 deletion remodels mitochondrial function.

• Loss of Qdr3 alters biofilm architecture and extracellular matrix production.

• qdr3 deletion enhances virulence.

• Qdr3 links membrane transport, mitochondrial function, and virulence.

Abstract

Candida auris (also known as Candidozyma auris) relies on extensive transporter networks to maintain cellular homeostasis and adapt to environmental stress, yet the broader regulatory roles of individual transporters remain poorly understood. Qdr3, a member of the major facilitator superfamily (MFS), contributes to multidrug resistance in several pathogenic yeasts, but its function in C. auris has not been defined. To investigate the role of Qdr3, we generated Δqdr3 mutants in C. auris strain B8441 and performed an integrated analysis combining phenotypic, ultrastructural, transcriptomic, proteomic, and virulence approaches. Deletion of qdr3 did not affect basal growth or antifungal susceptibility but was associated with extensive cellular remodeling. Transcriptomic profiling revealed extensive transcriptional remodeling, characterized by reduced expression of heat-shock and cell-surface maintenance pathways, alongside a strong induction of mitochondrial translation and biogenesis programs. These transcriptional shifts were supported by proteomic signatures and transmission electron microscopy, which revealed qualitative ultrastructural changes consistent with mitochondrial remodeling and enhanced cytoplasmic granularity. Qdr3 also influenced multicellular organization, as Δqdr3 biofilms exhibited reduced cellular aggregation and increased extracellular matrix production. In the Galleria mellonella infection model, Δqdr3 mutants displayed enhanced virulence despite reduced biofilm formation, highlighting a complex relationship between cellular remodeling and pathogenic potential. Together, these findings identify Qdr3 as a key regulator of cellular homeostasis, linking membrane transport, mitochondrial activity, and cell-surface architecture in C. auris. These results demonstrate how disruption of a single MFS transporter can drive extensive physiological and regulatory remodeling, ultimately altering virulence in this WHO critical priority pathogen.

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https://www.sciencedirect.com/science/article/pii/S266651742600101X