Document Type

Article

Version Deposited

Published Version

Publication Date

3-15-2015

Publication Title

Molecular Biology of the Cell

DOI

10.1091/mbc.E14-08-1315

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.

Comments

Molecular Biology of the Cell (MBoC) is an online journal published twice monthly and owned by the American Society for Cell Biology (ASCB). Unredacted accepted manuscripts are freely accessible immediately through MBoC In Press. Final published versions are freely accessible two months after publication at www.molbiolcell.org. MBoC is also available online through PubMed Central, sponsored by the U.S. National Library of Medicine.

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

Published Citation

Wang K, Yan R, Cooper KF, Strich R. Cyclin C mediates stress-induced mitochondrial fission and apoptosis. Mol Biol Cell. 2015 Mar 15;26(6):1030-43. Epub 2015 Jan 21. doi: 10.1091/mbc.E14-08-1315. PMID: 25609094. PMCID: PMC4357504.

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