Document Type

Article

Version Deposited

Published Version

Publication Date

12-5-2018

Publication Title

Molecular Biology of the Cell

DOI

10.1091/mbc.E18-07-0463

Abstract

Mitochondria exist in an equilibrium between fragmented and fused that shifts heavily toward fission in response to cellular damage. Nuclear to cytoplasmic cyclin C relocalization is essential for dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in response to oxidative stress. This study finds that cyclin C directly interacts with the Drp1 GTPase domain, increases its affinity to GTP and stimulates GTPase activity in vitro. In addition, the cyclin C domain that binds Drp1 is contained within the non-Cdk binding second cyclin box domain common to all cyclin family members. This interaction is important as this domain is sufficient to induce mitochondrial fission when expressed in mouse embryonic fibroblasts in the absence of additional stress signals. Using gel filtration chromatography and negative stain electron microscopy, we found that cyclin C interaction changes the geometry of Drp1 oligomers in vitro. High molecular weight low GTPase activity oligomers in the form of short filaments and rings were diminished while dimers and elongated filaments were observed. Our results support a model that cyclin C binding stimulates the reduction of low GTPase-activity Drp1 oligomers into dimers capable of producing high GTPase activity filaments.

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 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

Published Citation

Ganesan V, Willis SD, Chang KT, Beluch S, Cooper KF, Strich R. Cyclin C directly stimulates Drp1 GTP affinity to mediate stress-induced mitochondrial hyper-fission. Mol Biol Cell. 2018 Dec 5:mbcE18070463. doi: 10.1091/mbc.E18-07-0463. PMID: 30516433.

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