In response to cellular damage, the mitochondria undergo extensive fragmentation, exhibit mitochondrial outer membrane permeability (MOMP), and release pro-apoptotic factors. Although the basic fission machinery is required for this hyper-fission, the molecular switch that induces this process remained elusive. In response to oxidative stress, the yeast1 and mammalian2 transcription factor cyclin C translocate from the nucleus to the cytoplasm where they associate with the GTPase Drp1/DNM1 at the mitochondria. In both systems, cyclin C is both necessary and sufficient to induce extensive mitochondrial fragmentation. The conservation of cyclin C activity is remarkable as treating permeabilized mouse embryonic fibroblast cultures with purified yeast cyclin C rapidly induced complete mitochondrial fission without an added stress signal. Further analysis revealed that the mouse cyclin C is also required for stress-induced MOMP and apoptosis. Using a CCNC knockout MEF culture system, we found that cyclin C is required for efficient mitochondrial recruitment of the pro-apoptotic BH-3 protein BAX. This activity appears direct as cyclin C co-immunoprecipitates with activated BAX following oxidative stress. Consistent with the role in stress-induced apoptosis, we found that cyclin C suppresses hyperplasia and adenoma formation in a PTEN phosphatase thyroid tumor model. While either single mutant presents with a modest phenotype, combining Ccnc and Pten null alleles dramatically accelerates thyroid hyperplasia resulting in premature death. These results indicate that cyclin C is a previously undescribed solid tumor suppressor. These results suggest that cyclin C cytoplasmic localization alters mitochondrial dynamics and influences apoptotic sensitivity in mammals.
1Cooper et al., (2014) Dev. Cell. 28:161. 2Wang et al. (2015) Mol. Biol. Cell 26:1030.