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.

Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System

Mitochondria are essential for proper neuronal morphogenesis and functions, as they are the major source of energy for neural development. The dynamic morphology of mitochondria determines the key functions of mitochondria. Several regulatory proteins such as dynamin-related protein 1 (Drp1) are required to maintain mitochondrial morphology via a balance between continuous fusion and fission. Activity of Drp1, a key regulator in mitochondrial fission, is modulated by multiple post-translation modifications and receptor interactions. In addition, numerous researches have revealed that the regulation of Drp1 activity and mitochondrial dynamics is closely associated with several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. In this article, we concisely review the recent findings about the biological importance of Drp1-mediated mitochondrial fission in neurons under physiological and pathological conditions.

Changes in the Histone Acetylation Patterns during the Development of the Nervous System

Epigenetic modification such as DNA methylation and histone acetylation plays essential roles in many aspects of cellular function and development of animals. There is an increasing amounts of evidence for dynamic changes in the histone acetylation of specific gene segments, but little attempt was made to examine global pattern changes in the histone acetylation in developing nervous system. In this study, we found that acetylated histone H3 and H4 immunoreactivities were relatively weak in neuroepithelial cells in the ventricular zone of developing rat cerebral cortex or chick spinal cord, compared to the immature young neurons in the cortical plate of a rat embryo or lateral motor column in chick spinal cord. On the other hand, adult neural stem cells in the dentate gyrus (DG) of rat hippocampal formation did not exhibit such diminished histone acetylation, compared to neuroblasts and mature DG neurons. These results suggest that the level of histone acetylation is highly dynamic and tightly linked to the neuronal types and the differentiation stages.