The decision to undergo programmed cell death (PCD) is controlled by a complex interaction between nuclear and mitochondrial signals. The mitochondria are highly dynamic organelles that constantly undergo fission and fusion. However, one of the earliest PCD events is a dramatic shift in mitochondrial morphology toward fission. We have identified the transcription factor cyclin C as the biochemical trigger for stress-induced mitochondrial hyper-fragmentation in yeast (Cooper et al., 2014 Dev. Cell) and mammalian (Wang et al., 2015, MCB) cells. In response to PCD stimuli such as oxidative stress, cyclin C, but not its cognate kinase Cdk8, is released from the nucleus then associates with the fission machinery. Loss of cyclin C prevents mitochondrial fission while its ectopic introduction into the cytoplasm induces complete fragmentation in the absence of stress. The Cdk8 module subunit Med13 anchors cyclin C in the nucleus, and is degraded in response to oxidative stress. Deletion of MED13 results in mitochondrial hyperfragmentation in unstressed cells. Recent studies have found that mitochondrial fission occurs at junctions between the mitochondria and the endoplasmic reticulum (ER). We have found that the number of these junctions increases upon stress in a cyclin C-dependent manner. The results suggest that cyclin C plays a role in establishing and/or maintaining these stress-enhanced mitochondrial-ER junctions. In yeast, continuous cytoplasmic cyclin C causes constitutive mitochondrial fragmentation, stress hypersensitivity and loss of mtDNA integrity. Conversely, loss of cyclin C function protects cells from oxidative stress. The dual role for cyclin C couples the derepression of stress response genes with a mitochondrial fission program that can lead to cell death. In addition, these roles for cyclin C have been conserved from yeast to mammals.