Abstract
1 Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, State University of New York at Buffalo, Buffalo, NY, USA
2 Seattle Biomedical Research Institute, Seattle, WA, USA
3 Section of Infectious Diseases, University of Illinois at Chicago, Chicago, IL, USA
4 Section of Translational Mycology, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
The yeast-like fungus Cryptococcus neoformans favours respiration as a mechanism of energy production, and thus depends heavily on mitochondrial function. Previous studies of a C. neoformans vad1Δ mutant revealed reduced expression of the mitochondrial elongation factor TUF1 and defects in glycerol utilization, consistent with mitochondrial dysfunction. In this study, we found that in trans expression of TUF1 in the vad1Δ mutant suppressed the mitochondrial defects, including growth on respiration-dependent carbon sources and fluconazole resistance, associated with VAD1 deletion. Tetracycline, an inhibitor of mitochondrial translation, was found to confer resistance to fluconazole in the wild-type and vad1Δ mutant, whereas the fluconazole susceptibility of the TUF1-overexpressing strain was unaffected by tetracycline treatment. In the presence of fluconazole, the vad1Δ mutant exhibited increased activation of the global transcriptional regulator Sre1. TUF1 overexpression failed to alter cleavage of Sre1 in response to fluconazole in the vad1Δ mutant, suggesting that TUF1 repression in the vad1Δ mutant is distal to Sre1, or that it occurs through an independent pathway.