title: Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis.
abstract: Our published research has focused on the role of Goa1p, an apparent regulator of the Candida albicans mitochondrial complex I (CI). Lack of Goa1p affects optimum cell growth, CI activity and virulence. Eukaryotic CI is composed of a core of 14 alpha-proteobacterial subunit proteins and a variable number of supernumerary subunit proteins. Of the latter group of proteins, one (NUZM) is fungal specific and the other (NUXM) is found in fungi, algae and plants, but is not a mammalian CI subunit protein. We have established that NUXM is orf19.6607 and NUZM is orf19.287 in C. albicans. Herein, we validate both subunit proteins as NADH:ubiquinone oxidoreductases (NUO) and annotate their gene functions. To accomplish these objectives, we compared null mutants of each with wild type (WT) and gene-reconstituted strains. Genetic mutants of genes NUO1 (orf19.6607) and NUO2 (orf19.287), not surprisingly, each had reduced oxygen consumption, decreased mitochondrial redox potential, decreased CI activity, increased reactive oxidant species (ROS) and decreased chronological ageing in vitro. Loss of either gene results in disassembly of CI. Transcriptional profiling of both mutants indicated significant down-regulation of genes of carbon metabolism, as well as up-regulation of mitochondrial-associated gene families that may occur to compensate for the loss of CI activity. Profiling of both mutants also demonstrated a loss of cell wall β-mannosylation but not in a conserved CI subunit (ndh51Δ). The profiling data may indicate specific functions driven by the enzymatic activity of Nuo1p and Nuo2p. Of importance, each mutant is also avirulent in a murine blood-borne, invasive model of candidiasis associated with their reduced colonization of tissues. Based on their fungal specificity and roles in virulence, we suggest both as drug targets for antifungal drug discovery.
authors: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.|Chinese Academy of Medical Sciences (CAMS), Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Nanjing, China.
authors: Xiaodong
authors: X
authors: She
authors: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors: Kasra
authors: K
authors: Khamooshi
authors: Chinese Academy of Medical Sciences (CAMS), Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Nanjing, China.
authors: Yin
authors: Y
authors: Gao
authors: Chinese Academy of Medical Sciences (CAMS), Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Nanjing, China.
authors: Yongnian
authors: Y
authors: Shen
authors: Chinese Academy of Medical Sciences (CAMS), Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Nanjing, China.
authors: Yuxia
authors: Y
authors: Lv
authors: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors: Richard
authors: R
authors: Calderone
authors: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors: William
authors: W
authors: Fonzi
authors: Chinese Academy of Medical Sciences (CAMS), Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Nanjing, China.
authors: Weida
authors: W
authors: Liu
authors: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors: Dongmei
authors: D
authors: Li
mesh_terms: D000825:Animal Structures / Q000382:microbiology; D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000378:metabolism*; D058387:Candidemia / Q000382:microbiology / Q000473:pathology; D002473:Cell Wall / Q000378:metabolism*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D051379:Mice; D058977:Molecular Sequence Annotation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D037521:Virulence Factors; D042967:Electron Transport Complex I