title: The fungicide Mancozeb induces metacaspase-dependent apoptotic cell death in Saccharomyces cerevisiae BY4741.
abstract: Mancozeb (MZ), a mixture of ethylene-bis-dithiocarbamate manganese and zinc salts, is one of the most widely used fungicides in agriculture. Toxicologic studies in mammals and mammalian cells indicate that this fungicide can cause neurological and cytological disorders, putatively associated with pro-oxidant and apoptotic effects. Yeast adaptation to sub-inhibitory concentrations of MZ has been correlated with oxidative response, proteins degradation, and energy metabolism, and its main effect on yeast has been attributed to its high reactivity with thiol groups in proteins. Herein, we show that acute MZ treatments on aerobic exponentially growing yeast of wild type (BY4741) and deletion mutant strains, coupled with multiplex flow cytometry analysis, conclusively demonstrated that MZ displays the typical features of pro-oxidant activity on Saccharomyces, elevating mitochondrial ROS, and causing hyper-polarization of mitochondrial membranes leading to apoptosis. A drastic reduction of cellular viability associated with the maintenance of cell membrane integrity, as well as phosphatidyl serine externalization on yeast cells exposed to MZ, also supports an apoptotic mode of action. Moreover, abrogation of the apoptotic response in yca1 deficient mutants indicates that metacaspase-1 is involved in the programmed cell death mechanism induced by MZ in yeast.
authors.affiliation: Laboratory of Applied Microbiology, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco G. Vargas 1130, Caxias do Sul, Rio Grande do Sul, 95070-560, Brazil.
authors.forename: F J
authors.initials: FJ
authors.lastname: Scariot
authors.affiliation: Laboratory of Applied Microbiology, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco G. Vargas 1130, Caxias do Sul, Rio Grande do Sul, 95070-560, Brazil.
authors.forename: L M
authors.initials: LM
authors.lastname: Jahn
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Maianti
authors.affiliation: Laboratory of Applied Microbiology, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco G. Vargas 1130, Caxias do Sul, Rio Grande do Sul, 95070-560, Brazil.
authors.forename: A P L
authors.initials: AP
authors.lastname: Delamare
authors.affiliation: Laboratory of Applied Microbiology, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco G. Vargas 1130, Caxias do Sul, Rio Grande do Sul, 95070-560, Brazil. selaguna@ucs.br.|Cytogene Diagnósticos Moleculares Ltda., Lageado, Rio Grande do Sul, Brazil. selaguna@ucs.br.
authors.forename: S
authors.initials: S
authors.lastname: Echeverrigaray
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005659:Fungicides, Industrial / Q000494:pharmacology*; D008344:Maneb / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015038:Zineb / Q000494:pharmacology*
chemical_list: D005659:Fungicides, Industrial; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D008344:Maneb; D003546:Cysteine Endopeptidases; C013099:mancozeb; D015038:Zineb
keywords: Dithiocarbamate; Mitochondrial membrane potential; Programmed cell death; ROS; Yeast