Editors' ChoiceCell Biology

Cyclin C Moves Out of the Nucleus

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Science Signaling  04 Feb 2014:
Vol. 7, Issue 311, pp. ec33
DOI: 10.1126/scisignal.2005148

Mitochondria undergo fission and fusion in response to various physiological conditions, and disruption of the fission-fusion balance can cause pathological conditions, such as neurodegeneration. In yeast, oxidative stress stimulates mitochondrial fission and the release of proapoptotic factors from fragmented mitochondria. Cooper et al. report that, upon treatment with hydrogen peroxide to induce oxidative stress, the transcriptional repressor cyclin C (CycC) translocated from the nucleus to foci on the mitochondrial surface, where it transiently colocalized with Dnm1p before being degraded. Dnm1p is a dynamin-related guanosine triphosphatase that forms filaments around mitochondria that constrict to drive fission. Association of CycC with the mitochondrial outer membrane required the fission complex composed of Dnm1p, the Dnm1p receptor Fis1p, and the adaptor protein Mdv1p. Whereas most wild-type cells exhibited mitochondrial fragmentation after exposure to hydrogen peroxide or ethanol, only about 20% of cells lacking CycC (cncΔ) initiated fragmentation in response to these stressors. In the absence of stress, a mutant form of CycC, lacking transcriptional repressor activity and localizing to the cytosol, was present at mitochondria at sites of constriction and promoted fission, implying that CycC affected fission independently of its transcriptional role. Overexpression of fluorescently tagged, wild-type CycC was sufficient to induce fission in unstressed cells. Like Fis1p and Mdv1p, CycC was not required for oxidative stress–induced recruitment of Dnm1p to mitochondria but was required for Dnm1p foci to mature into the spiral filaments that drive fission. CycC was required for the redistribution of Mdv1p to sites of scission in response to oxidative stress, and these two proteins associated with one another in coimmunoprecipitation assays. Additional coimmunoprecipitation experiments using extracts from wild-type and cncΔ cells suggested that CycC promoted the interaction between Dnm1p and Mdv1p under oxidative stress. These results imply that the stress-induced nuclear-to-cytoplasmic translocation of CycC not only promotes apoptosis by relieving transcriptional repression of proapoptotic genes but also stimulates formation of the fission complex, thus coordinating the nuclear and mitochondrial response to stress. Commentary by Adachi and Sesaki considers the implications of these findings for mitochondrial fission driven by the Dnm1p homolog Drp1 in mammalian cells.

K. F. Cooper, S. Khakhina, S. K. Kim, R. Strich, Stress-induced nuclear-to-cytoplasmic translocation of cyclin C promotes mitochondrial fission in yeast. Dev. Cell 28, 161–173 (2014). [PubMed]

Y. Adachi, H. Sesaki, Cyclin C: An inducer of mitochondrial division hidden in the nucleus. Dev. Cell 28, 112–114 (2014). [PubMed]

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