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

Abstract

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][5][6][7][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].

Adaptive changes in the fungal cell wall mediate copper homeostasis

“…Also, it is not yet clear whether the cell wall changes in the cbi1 strain are directly related to Cbi1 function or whether they represent compensatory cellular changes in response to stress. This type of cell wall adaptation to cell stress is commonly observed in other conditions [48]. For example, cell wall chitin levels are increased in the human fungal pathogens Aspergillus fumigatus and C. neoformans during treatment with the beta-glucan synthase inhibitor capofungin [33].…”

Interactions between copper homeostasis and the fungal cell wall affect copper stress resistance

“…Also, it is not yet clear whether the cell wall changes in the cbi1 Δ strain are directly related to Cbi1 function or whether they represent compensatory cellular changes in response to stress. This type of cell wall adaptation to cell stress is commonly observed in other conditions [ 53 ]. For example, cell wall chitin levels are increased in the human fungal pathogens Aspergillus fumigatus and C .…”

Fusarium graminearumSte3 G-Protein Coupled Receptor: A Mediator of Hyphal Chemotropism and Pathogenesis

“…Although it is hard to predict in which morphogenetic changes these mitochondrial proteins might be involved, they are generally related to oxidative stress responses, based on mitochondria being major centers for the generation of hydrogen peroxide and reactive oxygen species (ROS), which are later taken up by the peroxisome. However, mitochondrial proteins have also been shown to directly influence fungal pathogenicity through phenotypic changes that involve cell wall modification, polysaccharide capsule modulation, the evasion of the host immune response, metabolic flexibility by alternating between carbon source utilization, and controlling cAMP/PKA signaling ( 53 , 54 ).…”