title: Mitochondrial sorting and assembly machinery subunit Sam37 in Candida albicans: insight into the roles of mitochondria in fitness, cell wall integrity, and virulence.
abstract: 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 (Sorting and Assembly Machinery) complex subunit Sam37 in Candida albicans. Inactivation of SAM37 in C. albicans leads to a large reduction in fitness, a phenotype not conserved with the model yeast Saccharomyces cerevisiae. Our data indicate that slow growth of the sam37ΔΔ mutant results from mitochondrial DNA loss, a new function for Sam37 in C. albicans, and from reduced activity of the essential SAM complex subunit Sam35. The sam37ΔΔ 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 in C. albicans. The sensitivity of the mutant to membrane-targeting antifungals was not significantly altered. The sam37ΔΔ 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 in C. 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qu
authors.forename: Branka
authors.initials: B
authors.lastname: Jelicic
authors.forename: Filomena
authors.initials: F
authors.lastname: Pettolino
authors.forename: Andrew
authors.initials: A
authors.lastname: Perry
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Lo
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Hewitt
authors.forename: Farkad
authors.initials: F
authors.lastname: Bantun
authors.forename: Traude H
authors.initials: TH
authors.lastname: Beilharz
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Peleg
authors.forename: Trevor
authors.initials: T
authors.lastname: Lithgow
authors.forename: Julianne T
authors.initials: JT
authors.lastname: Djordjevic
authors.forename: Ana
authors.initials: A
authors.lastname: Traven
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D058387:Candidemia / Q000382:microbiology; D002473:Cell Wall / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D025301:Hyphae / Q000378:metabolism; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000382:microbiology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009348:Nematoda / Q000382:microbiology; D053140:Organelle Shape; D010641:Phenotype; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D004272:DNA, Mitochondrial; D005656:Fungal Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D015725:Fluconazole