System-level impact of mitochondria on fungal virulence: to metabolism and beyond

Abstract

The mitochondrion plays wide-ranging roles in eukaryotic cell physiology. In pathogenic fungi, this central metabolic organelle mediates a range of functions related to disease, from fitness of the pathogen to developmental and morphogenetic transitions to antifungal drug susceptibility. In this review, we present the latest findings in this area. We focus on likely mechanisms of mitochondrial impact on fungal virulence pathways through metabolism and stress responses, but also potentially via control over signaling pathways. We highlight fungal mitochondrial proteins that lack human homologs, and which could be inhibited as a novel approach to antifungal drug strategy.

Keywords: Candida albicans; fungal pathogenesis; mitochondria.

Graphical Abstract Figure.

Pathogenic fungi cause a range of human infections, including invasive life-threatening disease. Here we discuss mitochondrial activity in fungal disease and therapeutic approaches.

Figure 1.

The mitochondrial biogenesis apparatus in C. albicans. Proteins required for mitochondrial protein import are shown. All components of the mitochondrial import apparatus as described in the model baker's yeast can be found by bioinformatics searches in C. albicans. TOM is the ‘gateway’ to mitochondria through which all imported proteins pass. TIM enables translocation into the matrix and targeting to the inner membrane. In C. albicans, some cytochromes (b2 and c1) follow a distinct route to the intermembrane space to what is known in S. cerevisiae. The pathways required for their mitochondrial import in C. albicans remain to be discovered. Candida albicans contains an additional Omp85 family member, Sam51, which is part of the SAM complex, and data suggest that SAM and ERMES are bridged together via Mdm10 (Victoria Hewitt, A.T. and Trevor Lithgow, in preparation). The Sam37 and Sam35 subunits of the SAM complex and entire ERMES complex are not conserved in humans, and Sam37 and Mmm1 have been found to be required for virulence of C. albicans in the systemic mouse model (Becker et al. ; Qu et al. 2012). Links between SAM and ERMES function and cell wall integrity and hyphal morphogenesis have been made (Dagley et al. ; Qu et al. 2012), reenforcing the concept that mitochondria have broad impact on pathways required for fungal pathogenesis.

Figure 2.

Cell wall changes upon respiratory dysfunction in the C. albicans goa1Δ mutant. The cell wall structures of WT (left) and the null goa1Δ (right) are shown. Cell wall polysaccharides and their linkages are color coded. In addition, phosphate, inositol and phosphate ceramide are shown as a GPI-anchored cell wall glycoprotein. Below the cell membrane, mitochondria are depicted with fewer mitochondrial ETC CI in the goa1Δ. The reduction of β-1,2 mannan and β-1,6 glucan (unpublished) is shown in the mutant cell wall.

Figure 3.

Left. A WT mitochondrion is shown with an intact CI–CV ETC chain (red squares). The five subunits of the ETC are shown as rectangles. As for the individual subunit proteins of CI mentioned below, Ndh51p is critically located at the ubiquinone reduction site within the CI where other NADH oxidoreductases are located. The location of Nuo1p and Nuo2p is not known. Right. The outer/inner membranes are shown. In the CI mutants as well as goa1Δ, a loss (disassembly) of the CI complex from the inner membrane is depicted. The CI in the WT is represented as larger in molecular mass versus the other complexes. For each mutant, the disassembly of the CI is represented. Table below. Upregulated and downregulated genes in each of the CI mutants and in the putative CI regulator (goa1Δ) are listed for specific gene categories. Nuo1p and Nuo2p are nearly functionally redundant. All of the mutants except goa1Δ have major upregulation in genes of the ETC complexes, except CI (left column). These data may suggest that mutants have ETC compensatory activities that include one of the two alternate oxidases AOX2 and the NDE1.

Figure 4.

Roles of mitochondrial activity in C. albicans morphogenesis and biofilm formation. Mitochondrial activity is necessary for the transition from yeast to hyphal growth, but in mature biofilms mitochondria might be repressed perhaps due to changes in nutrients or access to oxygen. Reduction of mitochondrial activity might be driving protection from stresses, such as oxidative stress, thereby promoting cellular fitness. Whether and how mitochondrial functions impact on antifungal susceptibility of Candida biofilms remains to be determined.