CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation

Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1S616 phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1S616 preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1’s fission-promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1S616 in post-mitotic neurons. Researchers in South Korea have mapped the pathway that controls the growth and division of mitochondria during maturation of nerve cells. During this process, mitochondria replicate by splitting in two in order to maintain synaptic activity and healthy nerve cell function. The final part of the division process is driven by dynamin-related protein 1 (Drp1), the activity of which can be affected by a chemical modification known as phosphorylation. A team led by Woong Sun from Korea University in Seoul examined the phosphorylation of Drp1 in rat brains and cultured human cortical neurons. They showed that Drp1 phosphorylation is carried out by cyclin-dependent kinase 5, an enzyme known to be involved in brain development. The researchers found that this phosphorylation inhibited Drp1 function, restricting its activity in promoting the division of mitochondria.