title: Med13p prevents mitochondrial fission and programmed cell death in yeast through nuclear retention of cyclin C.
abstract: The yeast cyclin C-Cdk8 kinase forms a complex with Med13p to repress the transcription of genes involved in the stress response and meiosis. In response to oxidative stress, cyclin C displays nuclear to cytoplasmic relocalization that triggers mitochondrial fission and promotes programmed cell death. In this report, we demonstrate that Med13p mediates cyclin C nuclear retention in unstressed cells. Deleting MED13 allows aberrant cytoplasmic cyclin C localization and extensive mitochondrial fragmentation. Loss of Med13p function resulted in mitochondrial dysfunction and hypersensitivity to oxidative stress-induced programmed cell death that were dependent on cyclin C. The regulatory system controlling cyclin C-Med13p interaction is complex. First, a previous study found that cyclin C phosphorylation by the stress-activated MAP kinase Slt2p is required for nuclear to cytoplasmic translocation. This study found that cyclin C-Med13p association is impaired when the Slt2p target residue is substituted with a phosphomimetic amino acid. The second step involves Med13p destruction mediated by the 26S proteasome and cyclin C-Cdk8p kinase activity. In conclusion, Med13p maintains mitochondrial structure, function, and normal oxidative stress sensitivity through cyclin C nuclear retention. Releasing cyclin C from the nucleus involves both its phosphorylation by Slt2p coupled with Med13p destruction.
authors: Department of Molecular Biology, Rowan University-School of Osteopathic Medicine, Stratford, NJ 08084.
authors: Svetlana
authors: S
authors: Khakhina
authors: Department of Molecular Biology, Rowan University-School of Osteopathic Medicine, Stratford, NJ 08084.
authors: Katrina F
authors: KF
authors: Cooper
authors: Department of Molecular Biology, Rowan University-School of Osteopathic Medicine, Stratford, NJ 08084 strichra@rowan.edu.
authors: Randy
authors: R
authors: Strich
mesh_terms: D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism*; D056745:Cyclin C / Q000378:metabolism*; D016213:Cyclins / Q000502:physiology*; D056892:Mediator Complex / Q000502:physiology*; D063154:Mitochondrial Dynamics; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D056745:Cyclin C; D016213:Cyclins; D056892:Mediator Complex; C093967:SSN2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C093345:SSN8 protein, S cerevisiae