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

Abstract

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 radiationinduced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.

The XBP1-MARCH5-MFN2 Axis Confers ER Stress Resistance by Coordinating Mitochondrial Fission and Mitophagy in Melanoma

“…Therefore, we proposed that MFN2 down-regulation may be responsible for ER stress-induced mitochondrial ssion and mitophagy. Of note, the phosphorylation of DRP1 was capable of sensing exogenous signal to regulate mitochondrial ssion [27][28][29], with phosphorylation at S616 promoting ssion whereas phosphorylation at S637 counteracting it [30]. The expression of phosphor-DRP1 at S637 displayed marginal alteration and the phosphor-DRP1 at S616 was signi cantly reduced ( Fig.…”

Three decades of Cdk5

“…As such, imbalanced fusion/fission leads to mitochondrial dysfunction and degeneration. Emerging evidence links Cdk5 hyperactivity to excessive mitochondrial fission under pathological conditions, such as neurotoxic insults and neurodegenerative diseases [120][121][122][123][124][125][126][127].…”

“…Drp1 is recruited from the cytosol to the mitochondrial outer membrane (MOM), where it assembles into ring-like structures that wrap around the MOM and incise the membrane following GTP hydrolysis [118]. In pathological conditions, Cdk5 phosphorylates Drp1 at S616, which increases its mitochondrial translocalization and GTPase activity, ultimately accelerating mitochondrial fission [120][121][122][123][124][125][126][127]. Excessive mitochondrial fission is associated with mitochondrial defects and neuronal death.…”

“…Excessive mitochondrial fission is associated with mitochondrial defects and neuronal death. Thus, pharmacological or genetic inhibition of Cdk5 restores mitochondrial ATP production and confers neuroprotection by attenuating Drp1-induced mitochondrial fission in disease models [120][121][122][123][124][125][126][127].…”

Mitochondria: Novel Mechanisms and Therapeutic Targets for Secondary Brain Injury After Intracerebral Hemorrhage

“…Under physiological conditions, mitochondrial fission is crucial for removing damaged mitochondria to maintain mitochondrial stability (Weir et al, 2017 ). However, excessive fission damages mitochondrial structure, leading to impaired respiratory function, increased mROS production, ATP deficiency, and apoptotic pathway activation (Nakamura and Lipton, 2011 ; Zhou et al, 2019 ; Rong et al, 2020 ).…”