title: Ceramide triggers metacaspase-independent mitochondrial cell death in yeast.
abstract: The activation of ceramide-generating enzymes, the blockade of ceramide degradation, or the addition of ceramide analogues can trigger apoptosis or necrosis in human cancer cells. Moreover, endogenous ceramide plays a decisive role in the killing of neoplastic cells by conventional anticancer chemotherapeutics. Here, we explored the possibility that membrane-permeable C2-ceramide might kill budding yeast (Saccharomyces cerevisiae) cells under fermentative conditions, where they exhibit rapid proliferation and a Warburg-like metabolism that is reminiscent of cancer cells. C2-ceramide efficiently induced the generation of reactive oxygen species (ROS), as well as apoptotic and necrotic cell death, and this effect was not influenced by deletion of the sole yeast metacaspase. However, C2-ceramide largely failed to cause ROS hypergeneration and cell death upon deletion of the mitochondrial genome. Thus, mitochondrial function is strictly required for C2-ceramide-induced yeast lethality. Accordingly, mitochondria from C2-ceramide-treated yeast cells exhibited major morphological alterations including organelle fragmentation and aggregation. Altogether, our results point to a pivotal role of mitochondria in ceramide-induced yeast cell death.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Didac
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.forename: Angela
authors.initials: A
authors.lastname: Reisenbichler
authors.forename: Petra
authors.initials: P
authors.lastname: Heimbucher
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bauer
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Braun
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Rockenfeller
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Fröhlich
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics; D049109:Cell Proliferation; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology*; D005285:Fermentation; D054629:Genome, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D002518:Ceramides; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D020169:Caspases