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

Abstract

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...

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