Translocation of SenP5 from the Nucleoli to the Mitochondria Modulates DRP1-dependent Fission during Mitosis

Abstract

The mechanisms that ensure an equal inheritance of cellular organelles during mitosis are an important area of study in cell biology. For the mitochondria fragment during mitosis, however, the cellular links that signal these changes are largely unknown. We recently identified a SUMO protease, SenP5, that deSUMOylates a number of mitochondrial targets, including the dynamin-related fission GTPase, DRP1. In interphase, SenP5 resides primarily within the nucleoli, in addition to a cytosolic pool. Here we report the relocalization of SenP5 from the nucleoli to the mitochondrial surface at G 2 /M transition prior to nuclear envelope breakdown. The recruitment of SenP5 results in a significant loss in mitochondrial SUMOylation, and a concomitant increase in the labile pool of DRP1 that drives mitochondrial fragmentation. Importantly, silencing of SenP5 leads to an arrest in the cell cycle precisely at the time when the protease is translocated to the mitochondria. These data indicate that transition of SenP5 to the mitochondria plays an important role in mitochondrial fragmentation during mitosis. The altered intracellular localization of SenP5 represents the first example of the mitochondrial recruitment of a SUMO protease and provides new insights into the mechanisms of interorganellar communication during the cell cycle.The regulation of the cell cycle is based upon a number of critical checkpoints that ensure the cell is healthy, the DNA is correctly replicated, there is sufficient metabolic energy, and that the organelles are properly partitioned during mitosis. Each of the cell cycle checkpoints are maintained through precise signaling cascades, whose activities determine whether the cycle proceeds, remains quiescent, or whether the cell may enter into apoptotic death. A complete understanding of all cell cycle checkpoints is critical for the identification of new therapeutic targets for both cancer and for the development of regenerative technologies. Recently, genetic models in Drosophila melanogaster have identified at least two novel retrograde signaling pathways that ensure sufficient metabolic capacity and health at the G 1 /S checkpoint (1, 2). Mutations in a component of electron transport chain complex IV led to a 60% decrease in cellular ATP, thereby activating AMP-activated protein kinase and p53-dependent degradation of cyclin E (1). In a parallel pathway, the increased production of cellular ROS through mutations in a component of complex I led to the activation of the c-Jun NH 2 -terminal kinase (JNK)-FOXO cascade that up-regulates the cyclin E inhibitor Dacapo, causing cell cycle arrest at G 1 /S (2). These two pathways highlight the emerging importance of the mitochondria as an essential component of intracellular signaling cascades and cell cycle regulation.The mitochondria cannot be formed de novo, therefore the proliferation and segregation of these organelles during mitosis may be just as important to cellular survival as their role in signaling the health of the cell during G 1 . Mitochondr...

Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans

“…Several studies indicate a close relationship between the rDNA arrays, ribosomal biogenesis and the mitochondria [10][11][12][13] . For instance, recent evidence points to the import of 5S rRNAs into the mitochondria through a highly regulated process 35,36 .…”

“…For instance, recent evidence points to the import of 5S rRNAs into the mitochondria through a highly regulated process 35,36 . Moreover, tight regulation of nuclear transcription ensures proper mitochondrial biogenesis 11,13 . As such, functional crosstalk between the rDNA dosage and the mitochondria might be manifested in natural populations.…”

“…1), are present at variable levels in cells and interact with nuclear ribosomes through coordinated processes [8][9][10] . Indeed, functional relationships between the rRNA transcription and the mitochondria are evident [10][11][12][13] . Finally, analyses in Drosophila indicated that the expression of genes that localize to the mitochondria is responsive to engineered deletions that decreased rDNA CN 8 .…”

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

“…Reduced dynamics accompanies the process of ageing [41], is associated with the development of neurodegenerative diseases [42][43][44] and plays an important role in the execution of apoptosis [45,46]. Repetitive fusion and fission of mitochondria during the cell cycle has to be regulated [47][48][49][50]; otherwise, the continuity of the mitochondrial genome is not properly guaranteed [51,52], resulting in mitochondrial heterogeneity and malfunction [53]. Obviously, mitochondrial dynamics is important for quality control [27,54].…”

Shaping the mitochondrion: mitochondrial biogenesis, dynamics and dysfunction

“…Studies of DRP1 post-translational modifications, including phosphorylation and SUMOylation, have yielded insight into the cellular mechanisms that regulate mitochondrial fission in mammals. H. McBride (Ottawa, ON, Canada) and colleagues previously showed that several mitochondrial proteins, including DRP1, are reversibly SUMOylated by the E3 ligase MAPL and the SUMO protease (Harder et al, 2004;Zunino et al, 2007Zunino et al, , 2009Braschi et al, 2009). In a surprising new twist to this story, McBride reported that SenP5 moves from the nucleolus to the mitochondrial surface during the G2/M phase of the cell cycle, where its deSUMOylation activity promotes DRP1 assembly and mitochondrial fission ).…”