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.
Animals ; Cells, Cultured ; Cyclin-Dependent Kinase 5/*metabolism ; Dynamins/analysis/*metabolism ; HeLa Cells ; Humans ; Mitochondria/metabolism ; Mitosis ; Neurons/*cytology/*metabolism ; Phosphorylation ; Rats

McCune-Albright syndrome (MAS) is a sporadic disease that's characterized by polyostotic fibrous dysplasia, cafe-au-lait pigmentation of the skin, and multiple endocrinopathies, including sexual precocity, hyperthyroidism, acromegaly, and hypercortisolism. Recent evidence has shown that the clinical manifestations are caused by a postzygotic activating missense mutation in the gene coding for the alpha-subunit of Gs protein that stimulates c-AMP formation in the affected tissues. Substitution of the Arg(201) residue in Gsalpha with cysteine or histidine have been identified in many MAS patients and Arg(201) to Gly or Leu mutations have also been recently identified. We identified the Arg(201) to His mutation in the gene encoding Gsalpha in the thyroid tissue from a 36-year-old man who was suffering with polyostotic fibrous dysplasia and hyperthyroidism.
Acromegaly ; Adult ; Clinical Coding ; Cushing Syndrome ; Cysteine ; Fibrous Dysplasia, Polyostotic* ; Histidine ; Humans ; Hyperthyroidism* ; Mutation, Missense ; Pigmentation ; Skin ; Thyroid Gland