Cyclin C: An Inducer of Mitochondrial Division Hidden in the Nucleus

Abstract

In response to cellular stress, mitochondria remodel their structure by organelle division and fusion. In this issue of Developmental Cell, Cooper et al. (2014) report that a nuclear protein, cyclin C, is recruited from nuclei to mitochondria upon oxidative stress and promotes mitochondrial division and apoptosis of the cell.

Mitochondria form tubular structures in many cell types (Sesaki et al., 2013). This morphology dramatically changes under a variety of physiological and pathological conditions – tubules become elongated and connected or they become fragmented (Figure 1). Three dynamin-related GTPases are central components that are involved in these dynamic processes and are conserved from yeast to humans. Dnm1p (yeast)/Drp1 (mammals) mediates mitochondrial division, whereas Fzo1p/mitofusin and Mgm1p/Opa1 mediate mitochondrial fusion. The localization, abundance, and activity of these GTPases are highly regulated to control the morphological balance. Relative activation of mitochondrial division over fusion results in fragmentation of mitochondria, whereas a reversal results in enlargement of mitochondria. The reorganization of mitochondria morphology plays active roles in facilitating cellular processes including cell proliferation, differentiation, cell death, and survival. Highlighting the importance of the control of morphological balance in human health, genetic and physiological alterations in the division and fusion components are associated with neurodegenerative and neurodevelopmental disorders (Itoh et al., 2013).

Figure 1.

The balance between mitochondrial division and fusion

Mitochondria fragmentation is often associated with various types of damage to cells or mitochondria (Figure 1) (Youle and van der Bliek, 2012). When cells undergo apoptosis and necroptosis in response to different death stimuli, mitochondria become fragmented through increased recruitment of Drp1 to mitochondria. Drp1 can facilitate the release of the proapoptotic factor cytochrome c from mitochondria by mechanical scission of the outer membrane or other remodeling mechanisms such as hemifusion (Montessuit et al., 2010). Abnormally small mitochondria may show altered bioenergetics, possibly due to alterations in the surface area-to-volume ratio. Aberrant stimulation of mitochondrial division is also linked to neuronal death in Alzheimer’s disease in which Drp1 has been reported to become activated by S-nitrosylation, promoting mitochondrial division (Cho et al., 2009). Mitophagy eliminates damaged mitochondria. During mitophagy, mitochondrial division can lead to efficient engulfment of mitochondria by autophagosomes by reducing the organelle size (Tanaka et al., 2010). Mitochondrial division can also physically separate damaged portions of the mitochondria from the remaining healthy portions of the mitochondria (Twig et al., 2008). This degradation process likely protects cells from toxic effects such as reactive oxygen species that are produced by dysfunctional mitochondria.

Yeast cells that are exposed to oxidative stress undergo apoptosis. Fragmentation of mitochondria facilitates cell death, and its inhibition in knockout strains lacking Dnm1p and its receptor Fis1p delays the process. Reporting in this issue of Developmental Cell, Cooper et al. (2014) discovered an unexpected role for a nuclear protein, cyclin C, inoxidative stress-induced mitochondrial fragmentation in yeast. Before this work, cyclin C, which is a member of the cyclin protein family, was shown to bind to the cyclin-dependent kinase Cdk8p and function as a transcription factor by associating with RNA polymerase II, thus controlling different processes including programed cell death. Intriguingly, the work of Cooper et al. (2014) revealed a role for cyclin C that is independent of its known function in transcription. When hydrogen peroxide was added to the yeast cell culture, cyclin C was transported out of the nucleus and formed foci on the surface of mitochondria. As cyclin C undergoes proteosomal degradation in the cytosol, cyclin C was only transiently localized to mitochondria, where it formed punctate structures. Despite its short life on mitochondria, cyclin C performed an important role in promoting mitochondrial division. The mitochondrial localization of cyclin C puncta depended on components of the division machinery. Dnm1p, its adaptor-receptor complex (Mdv1p-Fis1p), and cyclin C colocalized to Dnm1p-Mdv1p foci. Cyclin C strengthened stress-induced association of Dnm1p with Mdv1p and therefore stimulated mitochondrial division. Supporting the dual role of cyclin C as a proapoptotic factor in gene expression and in mitochondrial division, yeast mutants lacking cyclin C were more resistant to hydrogen peroxide compared with fis13 mutants, which were only defective in mitochondrial division. Remarkably, cytoplasmic cyclin C was sufficient to stimulate mitochondrial division, as overexpression of cyclin C or mutant cyclin C defective in nuclear retention induced mitochondrial fragmentation in the absence of oxidative stress. Cyclin C, a potent division inducer, appeared to be sequestered in the nuclei waiting for stimuli. These fascinating discoveries greatly advance our understanding of the mechanisms underlying the regulation of mitochondrial dynamics in cellular stress responses.

The findings of Cooper et al. (2014) raise a number of important questions. Clearly, deciphering how cyclin C stimulates Dnm1p-Mdv1p interactions and mitochondrial division will be of great interest. Because cyclin C is subject to degradation in the cytosol, the cyclin C-mediated mechanism may be catalytic or stimulate a positive feedback mechanism for mitochondrial division. A variety of posttranslational modifications have been reported for regulation of mitochondrial division including phosphorylation, ubiquitination, sumoylation, and S-nitrosylation. Because cyclin C regulates cyclin-dependent kinases, cyclin C may direct phosphorylation of division components through cytosolic protein kinases upon association with Mdv1p. Cyclin C may also initiate nucleation of Dnm1p as a guanine nucleotide exchange factor and stimulate its polymerization. This function may be accomplished by relatively small amounts of cyclin C. As Mdv1p preferentially binds to a GTP-bound form of Dnm1p, this activity could account for the stabilization of Dnm1p-Mdv1p association (Lackner et al., 2009). Another question is the conservation of the mitochondrial role of cyclin C in higher organisms. As both cyclin C and the mitochondrial division machinery are evolutionarily well conserved from yeast to humans, similar mechanisms may operate in mammalian cells. However, mitochondrial recruitment of mammalian Drp1 is different from yeast Dnm1p: instead of using the two-component system (Fis1p-Mdv1p) in yeast, minimum division machinery can be assembled by Drp1 and one of its receptor proteins such as Mf for MiD/MIEF, and adaptor proteins like Mdv1p seem to be unnecessary (Koirala et al., 2013). Future studies of cyclin C will provide a new level of understanding of the role of mitochondrial dynamics in mammals based on the groundbreaking work by Cooper et al. (2014) in the yeast system.

Mitochondria continuously divide and fuse at similar rates to maintain an overall, steady-state morphology. In response to different stimuli, the balance tips to fragmentation due to relative activation of division or interconnection due to relative activation of fusion.