Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy

• Published in: Cell death & disease Vol. 11; no. 9; p. 720
• Main Authors: Rong, Rong, Xia, Xiaobo, Peng, Haiqin, Li, Haibo, You, Mengling, Liang, Zhuotao, Yao, Fei, Yao, Xueyan, Xiong, Kun, Huang, Jufang, Zhou, Rongrong, Ji, Dan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-09-2020; Springer Nature B.V
• Subjects: 13; 13/89; 14; 14/19; 631/378/340; 64; 64/60; 692/699/375; 82; 82/29; 96; 96/1; Animals; Antibodies; Apoptosis; Apoptosis - radiation effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - antagonists & inhibitors; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Dynamin; Dynamins - antagonists & inhibitors; Dynamins - metabolism; Humans; Immunology; Life Sciences; Male; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria - metabolism; Mitochondria - radiation effects; Mitochondrial Dynamics - radiation effects; Neurons - metabolism; Neurons - pathology; Neurons - radiation effects; Optic Nerve Diseases - blood; Optic Nerve Diseases - etiology; Optic Nerve Diseases - metabolism; Optic Nerve Diseases - pathology; Optic neuropathy; Phosphorylation; Quinazolinones - pharmacology; Radiation Injuries, Experimental - metabolism; Radiation therapy; Radiotherapy - adverse effects; Rats; Reactive oxygen species; Roscovitine; Roscovitine - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02922-y

Radiation-induced optic neuropathy (RION) is a devastating complication following external beam radiation therapy (EBRT) that leads to acute vision loss. To date, no efficient, available treatment for this complication, due partly to the lack of understanding regarding the developmental processes behind RION. Here, we report radiation caused changes in mitochondrial dynamics by regulating the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission-1 (Fis1). Concurrent with an excessive production of reactive oxygen species (ROS), both neuronal injury and visual dysfunction resulted. Further, our findings delineate an important mechanism by which cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of Drp1 (Ser616) regulates defects in mitochondrial dynamics associated with neuronal injury in the development of RION. Both the pharmacological inhibition of Cdk5 by roscovitine and the inhibition of Drp1 by mdivi-1 inhibited mitochondrial fission and the production of ROS associated with radiation-induced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.