title: Cyclin C mediates stress-induced mitochondrial fission and apoptosis.
abstract: Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. Cyclin C-Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEFs), we demonstrate that cyclin C directs the extensive mitochondrial scission induced by the anticancer drug cisplatin or oxidative stress. This activity is independent of transcriptional regulation, as Cdk8 is not required for this activity. Furthermore, adding purified cyclin C to unstressed permeabilized MEF cultures induced complete mitochondrial fragmentation that was dependent on the fission factors Drp1 and Mff. To regulate fission, a portion of cyclin C translocates from the nucleus to the cytoplasm, where it associates with Drp1 and is required for its enhanced mitochondrial activity in oxidatively stressed cells. In addition, although HeLa cells regulate cyclin C in a manner similar to MEF cells, U2OS osteosarcoma cultures display constitutively cytoplasmic cyclin C and semifragmented mitochondria. Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membrane permeability and apoptosis in cells treated with cisplatin. In conclusion, this study suggests that cyclin C connects stress-induced mitochondrial hyperfission and programmed cell death in mammalian cells.
authors.affiliation: Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08055.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08055.
authors.forename: Ruilan
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08055.
authors.forename: Katrina F
authors.initials: KF
authors.lastname: Cooper
authors.affiliation: Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08055 strichra@rowan.edu.
authors.forename: Randy
authors.initials: R
authors.lastname: Strich
mesh_terms: D000818:Animals; D017209:Apoptosis; D056745:Cyclin C / Q000502:physiology*; D034281:Dynamins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D021381:Protein Transport; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: C503675:Ccnc protein, mouse; D056745:Cyclin C; C486391:Dnm1l protein, mouse; D034281:Dynamins