Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy.
Animals
Apoptosis
/ radiation effects
Cyclin-Dependent Kinase 5
/ antagonists & inhibitors
Dynamins
/ antagonists & inhibitors
Humans
Male
Mice
Mice, Inbred BALB C
Mitochondria
/ metabolism
Mitochondrial Dynamics
/ radiation effects
Neurons
/ metabolism
Optic Nerve Diseases
/ blood
Phosphorylation
Quinazolinones
/ pharmacology
Radiation Injuries, Experimental
/ metabolism
Radiotherapy
/ adverse effects
Rats
Roscovitine
/ pharmacology
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
03 09 2020
03 09 2020
Historique:
received:
10
10
2019
accepted:
24
08
2020
revised:
22
08
2020
entrez:
5
9
2020
pubmed:
5
9
2020
medline:
28
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32883957
doi: 10.1038/s41419-020-02922-y
pii: 10.1038/s41419-020-02922-y
pmc: PMC7473761
doi:
Substances chimiques
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
0
Quinazolinones
0
Roscovitine
0ES1C2KQ94
Cyclin-Dependent Kinase 5
EC 2.7.11.1
Cdk5 protein, mouse
EC 2.7.11.22
Cdk5 protein, rat
EC 2.7.11.22
Dnm1l protein, mouse
EC 3.6.5.5
Dnm1l protein, rat
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
720Références
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