Respiring to infect: Emerging links between mitochondria, the electron transport chain, and fungal pathogenesis

Fungal pathogens threaten human health both directly as infectious agents and indirectly by limiting crop production, and new approaches are desperately needed to combat fungal diseases [1]. There is a growing appreciation that mitochondrial functions contribute to the ability of fungal pathogens to cause disease and may be promising targets for new therapeutic approaches [2,3]. A number of excellent reviews provide insights into the roles of mitochondria in fungal pathogens; readers are directed to these reviews for information on connections between mitochondria and virulence, antifungal drug resistance and susceptibility, and cell wall synthesis [4–8]. Our intention in this review is to focus on recent studies that highlight mitochondrial connections to virulence, metal homeostasis, the response to stress, and metabolic adaptation, as summarized in Fig 1, for a selected set of fungi that are major agents of human disease: Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans [9]. A. fumigatus is the causative agent of noninvasive pulmonary infections (aspergillomas and chronic aspergillosis), allergic bronchopulmonary aspergillosis, and invasive pulmonary aspergillosis. C. albicans is a commensal in the human gut but can cause invasive candidiasis of the blood stream and internal organs, as well as diseases involving mucosal surfaces. Infections with C. neoformans generally begin in lung tissue, but the fungus has a propensity to disseminate to the brain to cause meningoencephalitis, a disease that is highly prevalent and often fatal in the HIV/AIDS population. These fungi have aerobic lifestyles dependent on mitochondria, and the involvement of the electron transport chain (ETC) emerges as a common theme in their ability to cause disease (Fig 2) [5,10,11]. Open in a separate window Fig 1 Mitochondrial-associated activities that impact fungal pathogenesis. Mitochondria play key roles in stress responses and metabolic activities (e.g., iron homeostasis and use of carbon sources) relevant to fungal proliferation in mammalian hosts. Recent studies emphasize the prominent participation of the ETC in virulence, and the targets of inhibitors of specific complexes are shown in Fig 2. The phenotypic outcomes of perturbed mitochondrial function include cell surface changes that directly influence evasion of the host immune response. Critically important activities related to drug susceptibility and resistance are the subject of other recent reviews [2–9]. cAMP, cyclic adenosine monophosphate; ETC, electron transport chain; PKA, protein kinase A; ROS, reactive oxygen species.

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