title: Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast Candida glabrata.
abstract: Candida glabrata, a haploid budding yeast, is the cause of severe systemic infections in immune-compromised hosts. The amount of free iron supplied to C. glabrata cells during systemic infections is severely limited by iron-chelating proteins such as transferrin. Thus, the iron-deficiency response in C. glabrata cells is thought to play important roles in their survival inside the host's body. In this study, we found that mitophagy was induced under iron-depleted conditions, and that the disruption of a gene homologous to ATG32, which is responsible for mitophagy in Saccharomyces cerevisiae, blocked mitophagy in C. glabrata. The mitophagic activity in C. glabrata cells was not detected on short-period exposure to nitrogen-starved conditions, which is a mitophagy-inducing condition used in S. cerevisiae. The mitophagy-deficient atg32Δ mutant of C. glabrata also exhibited decreased longevity under iron-deficient conditions. The mitochondrial membrane potential in Cgatg32Δ cells was significantly lower than that in wild-type cells under iron-depleted conditions. In a mouse model of disseminated infection, the Cgatg32Δ strain resulted in significantly decreased kidney and spleen fungal burdens compared with the wild-type strain. These results indicate that mitophagy in C. glabrata occurs in an iron-poor host tissue environment, and it may contribute to the longevity of cells, mitochondrial quality control, and pathogenesis.
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Nagi
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.|b Department of Food Science and Human Nutrition , Faculty of Agriculture, Ryukoku University , Otsu , Shiga , Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: c Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka , Mie , Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Ueno
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagoe
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umeyama
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.|d Department of Infectious Diseases and Infection Control , Saitama Medical Center, Saitama Medical University , Saitama , Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohno
authors.affiliation: a Department of Chemotherapy and Mycoses , National Institute of Infectious Diseases , Shinjuku-ku , Tokyo , Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D041221:Candida glabrata / Q000378:metabolism*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007501:Iron / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: C543183:Atg32 protein, S cerevisiae; D000071183:Autophagy-Related Proteins; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins; D007501:Iron; D009584:Nitrogen
keywords: Atg32; Candida; autophagy; iron; mitochondria; mitophagy; pathogenicity; yeast