Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

Recent studies indicate that mitochondrial functions impinge on cell wall integrity, drug tolerance, and virulence of human fungal pathogens. However, the mechanistic aspects of these processes are poorly understood. We focused on the mitochondrial outer membrane SAM (S orting andA ssemblyM achinery) complex subunit Sam37 inCandida albicans . Inactivation ofSAM37 inC. albicans leads to a large reduction in fitness, a phenotype not conserved with the model yeastSaccharomyces cerevisiae . Our data indicate that slow growth of thesam37ΔΔ mutant results from mitochondrial DNA loss, a new function for Sam37 inC. albicans , and from reduced activity of the essential SAM complex subunit Sam35. Thesam37ΔΔ mutant was hypersensitive to drugs that target the cell wall and displayed altered cell wall structure, supporting a role for Sam37 in cell wall integrity inC. albicans . The sensitivity of the mutant to membrane-targeting antifungals was not significantly altered. Thesam37ΔΔ mutant was avirulent in the mouse model, and bioinformatics showed that the fungal Sam37 proteins are distant from their animal counterparts and could thus represent potential drug targets. Our study provides the first direct evidence for a link between mitochondrial function and cell wall integrity inC. albicans and is further relevant for understanding mitochondrial function in fitness, antifungal drug tolerance, and virulence of this major pathogen. Beyond the relevance to fungal pathogenesis, this work also provides new insight into the mitochondrial and cellular roles of the SAM complex in fungi.