CaMK II -induced Drp1 phosphorylation contributes to blue light-induced AIF-mediated necroptosis in retinal R28 cells
Dawei Yang1, Rong Rong2, Rongliang Yang2
1The School of Life Sciences, Central South University, Changsha, 410078, Hunan Province, China; Eye Center of Xiangya Hospital and Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, 410008, Hunan Province, China.
Abstract:
Retinal damage caused by blue light has become an important public health concern. Mitochondria have been found to play a key role in light-induced retinal cell death. In this study, we aimed to clarify the molecular mechanism involved in mitochondrion-related retinal cell damage caused by blue light, the major component of light-emitting diodes (LEDs). Our results show that blue light (450 nm, 300lux)-induced R28 cell death is caspase independent and can be attenuated by necrostatin-1. Apoptosis-inducing factor (AIF) cleavage and translocation to the nucleus are involved in the cell death progress. Blue light exposure causes mitochondrial fragmentation, which is mediated by phosphorylation at dynamin-related protein 1 (Drp1) Ser616 site, but it does not alter the protein levels of fission or fusion machinery. Knocking down Drp1 or treatment with Drp1 inhibitor Mdivi-1 protects R28 cells from blue light. Overproduction of reactive oxygen species (ROS) is induced by blue light. The ROS scavenger Trolox decreases Drp1 Ser616 phosphorylation level and mitochondrial fragmentation upon blue light exposure. Moreover, Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 blocks Drp1 phosphorylation and rescues mitochondrial fragmentation and AIF-mediated cell death caused by blue light. In conclusion, our data suggest that the CaMKII-Drp1 pathway plays a major role in blue light-induced AIF-mediated retinal cell damage.
Insights
Blue light exposure causes retinal cell death through a CaMKII-Drp1 pathway, leading to mitochondrial damage and apoptosis-inducing factor release. This mechanism highlights potential therapeutic targets for preventing light-induced eye damage.
Area of Science:
- Ophthalmology
- Cell Biology
- Toxicology
Background:
- Blue light exposure is a growing public health concern linked to retinal damage.
- Mitochondria are critical in light-induced retinal cell death pathways.
- Understanding the molecular mechanisms of blue light-induced retinal damage is essential.
Purpose of the Study:
- To elucidate the molecular mechanisms of mitochondrion-related retinal cell damage induced by blue light from LEDs.
- To investigate the role of specific signaling pathways and proteins in blue light-induced R28 cell death.
Main Methods:
- Utilized R28 cells exposed to blue light (450 nm, 300 lux).
- Investigated cell death pathways (caspase-independent), mitochondrial dynamics (Drp1 phosphorylation), reactive oxygen species (ROS) production, and apoptosis-inducing factor (AIF) translocation.
- Employed genetic knockdown (Drp1) and pharmacological inhibitors (necrostatin-1, Mdivi-1, Trolox, KN93).
Main Results:
- Blue light-induced R28 cell death is caspase-independent and necrostatin-1 sensitive, involving AIF.
- Mitochondrial fragmentation is mediated by CaMKII-dependent Drp1 phosphorylation at Ser616, independent of overall fission/fusion protein levels.
- ROS production is induced by blue light, and scavenging ROS reduces Drp1 phosphorylation and mitochondrial fragmentation.
- Inhibition of CaMKII or Drp1 prevents mitochondrial fragmentation and AIF-mediated cell death.
Conclusions:
- The CaMKII-Drp1 signaling pathway is a key mediator of blue light-induced retinal cell damage.
- Blue light exposure triggers mitochondrial dysfunction and AIF-mediated cell death via this pathway.
- Targeting the CaMKII-Drp1 axis offers a potential therapeutic strategy for mitigating blue light-induced retinal injury.
