Biological consequences of petite mutations in Candida glabrata

Brun, Sophie; Dalle, Frédéric; Saulnier, Patrick; Rénier, Gilles; Bonnin, Alain; Chabasse, Dominique; Bouchara, Jean‐Philippe

doi:10.1093/jac/dki200

Cited by 57 publications

(61 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specific mitochondrial mutations in C. albicans, Candida glabrata, and S. cerevisiae lead to either resistance or hypersensitivity to antifungal drugs that target cell membranes, such as the azoles and the polyenes (9,10,15,16,23,24,36,(62)(63)(64)67). In particular, loss of mtDNA is known to lead to drug resistance, including resistance to the azole class of antifungal drugs (15,26,27,36,62,63,66; reviewed in reference 64).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

Jeličić

Pettolino

et al. 2012

Eukaryot Cell

View full text Add to dashboard Cite

f Recent studies indicate that mitochondrial functions impinge on cell wall integrity, drug tolerance, and virulence of human fungal pathogens. However, the mechanistic aspects of these processes are poorly understood. We focused on the mitochondrial outer membrane SAM (Sorting and Assembly Machinery) complex subunit Sam37 in Candida albicans. Inactivation of SAM37 in C. albicans leads to a large reduction in fitness, a phenotype not conserved with the model yeast Saccharomyces cerevisiae. Our data indicate that slow growth of the sam37⌬⌬ mutant results from mitochondrial DNA loss, a new function for Sam37 in C. albicans, and from reduced activity of the essential SAM complex subunit Sam35. The sam37⌬⌬ mutant was hypersensitive to drugs that target the cell wall and displayed altered cell wall structure, supporting a role for Sam37 in cell wall integrity in C. albicans. The sensitivity of the mutant to membrane-targeting antifungals was not significantly altered. The sam37⌬⌬ mutant was avirulent in the mouse model, and bioinformatics showed that the fungal Sam37 proteins are distant from their animal counterparts and could thus represent potential drug targets. Our study provides the first direct evidence for a link between mitochondrial function and cell wall integrity in C. albicans and is further relevant for understanding mitochondrial function in fitness, antifungal drug tolerance, and virulence of this major pathogen. Beyond the relevance to fungal pathogenesis, this work also provides new insight into the mitochondrial and cellular roles of the SAM complex in fungi.

show abstract

Section: Resultsmentioning

confidence: 99%

Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

Jeličić

Pettolino

et al. 2012

Eukaryot Cell

View full text Add to dashboard Cite

show abstract

“…C. glabrata clinical isolates that were converted to petite status by either ethidium bromide or fluconazole treatment were found to have reduced virulence in a mouse model of fungal pathogenesis (11). One concern with these experiments (noted by the authors of that study) is that evaluation of virulence was carried out without the administration of fluconazole.…”

Section: Candida Glabratamentioning

confidence: 99%

Multidrug Resistance in Fungi

2007

View full text Add to dashboard Cite

“…These studies suggest that the functions of mitochondria in these pathways are complex. With antifungal drugs that target cell membranes, such as the azoles and the polyenes, both resistance and sensitivity of mitochondrial mutants have been reported (9,10,18,22,45,75,85,86). In contrast, only sensitivity has been observed with agents that target the cell wall, which includes the echinocandin class of antifungal drugs (3,15,17,22,38,90).…”

mentioning

confidence: 99%

Mitochondria and Fungal Pathogenesis: Drug Tolerance, Virulence, and Potential for Antifungal Therapy

2011

View full text Add to dashboard Cite

Recently, mitochondria have been identified as important contributors to the virulence and drug tolerance of human fungal pathogens. In different scenarios, either hypo-or hypervirulence can result from changes in mitochondrial function. Similarly, specific mitochondrial mutations lead to either sensitivity or resistance to antifungal drugs. Here, we provide a synthesis of this emerging field, proposing that mitochondrial function in membrane lipid homeostasis is the common denominator underlying the observed effects of mitochondria in drug tolerance (both sensitivity and resistance). We discuss how the contrasting effects of mitochondrial dysfunction on fungal drug tolerance and virulence could be explained and the potential for targeting mitochondrial factors for future antifungal drug development.Although it has been studied quite extensively in the model yeast Saccharomyces cerevisiae, mitochondrial function has remained understudied in human fungal pathogens. A possible reason is that several pathogenic fungi, such as Candida albicans and Cryptococcus neoformans, are so-called "petite-negative" yeasts, i.e., they cannot survive mitochondrial genome loss, which is a classic and extensively used tool for studying mitochondrial function in S. cerevisiae. Recent work from several laboratories has revealed that mitochondria have a fundamental role as a control point in the cellular networks impacted by antifungal drugs, as well as a prominent role in fungal virulence. These studies suggest that the functions of mitochondria in these pathways are complex. With antifungal drugs that target cell membranes, such as the azoles and the polyenes, both resistance and sensitivity of mitochondrial mutants have been reported (9,10,18,22,45,75,85,86). In contrast, only sensitivity has been observed with agents that target the cell wall, which includes the echinocandin class of antifungal drugs (3,15,17,22,38,90). A similarly complex picture is observed in regard to virulence of mitochondrial mutants, with both hypo-and hypervirulence of Candida spp. mitochondrial mutants observed in animal infection models (1,4,10,19,25,64). These studies pose several questions. What is the biochemical basis for the impact of mitochondria on drug tolerance? When (and why) does a change to mitochondrial function lead to hypo-versus hypervirulence? Would mitochondrial factors be useful targets for antifungal drug development? In this review, we will consider the molecular and cellular mechanisms behind the observed drug sensitivity and virulence phenotypes of mitochondrial mutants, mostly discussing Candida spp., for which the most is known, and mentioning the other pathogens where appropriate. We will also draw on the model fungus S. cerevisiae, because mitochondrial functions have been extensively studied in this yeast and there is reasonable evidence that the mechanisms of mitochondrial involvement in drug resistance are conserved with pathogenic fungi. Finally, we will discuss the potential for targeting mitochondrial factors for the deve...

show abstract

Biological consequences of petite mutations in Candida glabrata

Abstract: This low virulence in mice suggests that petite mutants could be disregarded clinically although they may arise during fluconazole therapy.

Cited by 57 publications

References 34 publications

Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

Multidrug Resistance in Fungi

Mitochondria and Fungal Pathogenesis: Drug Tolerance, Virulence, and Potential for Antifungal Therapy

Contact Info

Product

Resources

About