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

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