Abstract
Candida albicans is an opportunistic fungal pathogen of major clinical concern. The virulence of this pathogen is intimately intertwined with its metabolism. Mitochondria, which have a central metabolic role, have undergone many lineage-specific adaptations in association with their eukaryotic host. A screen for lineage-specific genes identified seven such genes specific to the CTG clade of fungi, of which C. albicans is a member. Each is required for respiratory growth and is integral to expression of complex I, III, or IV of the electron transport chain. Two genes, NUO3 and NUO4, encode supernumerary subunits of complex I, whereas NUE1 and NUE2 have nonstructural roles in expression of complex I. Similarly, the other three genes have nonstructural roles in expression of complex III (QCE1) or complex IV (COE1 and COE2). In addition to these novel additions, an alternative functional assignment was found for the mitochondrial protein encoded by MNE1MNE1 was required for complex I expression in C. albicans, whereas the distantly related Saccharomyces cerevisiae ortholog participates in expression of complex III. Phenotypic analysis of deletion mutants showed that fermentative metabolism is unable to support optimal growth rates or yields of C. albicans However, yeast-hypha morphogenesis, an important virulence attribute, did not require respiratory metabolism under hypoxic conditions. The inability to respire also resulted in hypersensitivity to the antifungal fluconazole and in attenuated virulence in a Galleria mellonella infection model. The results show that lineage-specific adaptations have occurred in C. albicans mitochondria and highlight the significance of respiratory metabolism in the pathobiology of C. albicansIMPORTANCECandida albicans is an opportunistic fungal pathogen of major clinical concern. The virulence of this pathogen is intimately intertwined with its metabolic behavior, and mitochondria have a central role in that metabolism. Mitochondria have undergone many evolutionary changes, which include lineage-specific adaptations in association with their eukaryotic host. Seven lineage-specific genes required for electron transport chain function were identified in the CTG clade of fungi, of which C. albicans is a member. Additionally, examination of several highly diverged orthologs encoding mitochondrial proteins demonstrated functional reassignment for one of these. Deficits imparted by deletion of these genes revealed the critical role of respiration in virulence attributes of the fungus and highlight important evolutionary adaptations in C. albicans metabolism.
Highlights
Candida albicans is an opportunistic fungal pathogen of major clinical concern
Orthologs of GOA1, which is required for complex I function in C. albicans, are confined to the CTG clade of fungi [8]
Assessing multiple orthologs of slightly differing sequence was intended to eliminate fortuitous false positives, as all orthologs should embody the characteristics of a mitochondrial protein regardless of sequence variation
Summary
Candida albicans is an opportunistic fungal pathogen of major clinical concern. The virulence of this pathogen is intimately intertwined with its metabolism. IMPORTANCE Candida albicans is an opportunistic fungal pathogen of major clinical concern The virulence of this pathogen is intimately intertwined with its metabolic behavior, and mitochondria have a central role in that metabolism. Avirulence is likely multifactorial, as mitochondrial mutations negatively impact growth rates and carbon source utilization [7, 8, 13], cell wall structure [7, 9, 14, 15], membrane composition [15], morphogenesis [7, 8, 13, 16, 17], and biofilm formation [18], as well as interactions with neutrophils [19] and macrophages [20] These observations emphasize the decisive role of mitochondria in the pathobiology of C. albicans (reviewed in reference 21). The significance of mitochondria extends well beyond a basic understanding of metabolism and virulence, as mitochondrial mutations have a meaningful impact on antifungal susceptibility [7, 11, 22]
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