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: Kun Wang, Ruilan Yan, Katrina F Cooper, Randy Strich
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 26 Issue 6 Pg. 1030-43 (Mar 15 2015) ISSN: 1939-4586 [Electronic] United States
• PMID: 25609094 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Chemical References

• Ccnc protein, mouse
• Cyclin C
• Dnm1l protein, mouse
• Dynamins

Topics

• Animals
• Apoptosis
• Cyclin C (physiology)
• Dynamins (metabolism)
• HeLa Cells
• Humans
• Mice
• Mitochondria (metabolism)
• Mitochondrial Dynamics
• Protein Transport
• Signal Transduction
• Stress, Physiological