CaMK2A overexpression activates CREB signaling-dependent mitophagy and induces neuronal apoptosis in diabetes retinopathy

Abstract Background Diabetic retinopathy (DR) is a common complication of diabetes mellitus, characterized by progressive neurodegeneration and vision impairment. The Ca2+/calmodulin-dependent protein kinase II alpha (CaMK2A) and cAMP response element-binding protein (CREB) signaling pathway has been implicated in various neurological disorders. However, its role in DR pathogenesis remains elusive. Methods We established a DR mouse model by streptozotocin administration and performed histological, biochemical, and molecular analyses to investigate the involvement of CaMK2A/CREB signaling and its interplay with mitophagy. Additionally, we employed in vitro high-glucose (HG) treatment in immortalized RGC-5 cell line to dissect the underlying mechanisms. Pharmacological and genetic modulations were utilized to target CaMK2A/CREB pathway and mitophagy. Results In the DR model, we observed retinal degeneration, increased apoptosis, and reduced neurotransmitter production, accompanied by enhanced mitophagy and activation of the CaMK2A/CREB pathway. HG induction in RGC-5 cells recapitulated these findings, and autophagy inhibition partially rescued cell death but failed to suppress CaMK2A/CREB activation, suggesting mitophagy as a downstream consequence. CaMK2A knockdown or CREB phosphorylation inhibition attenuated HG-induced mitophagy, apoptosis, and neurotransmitter depletion, while CREB activation exacerbated these effects. CaMK2A silencing mitigated DR progression, oxidative stress, inflammation, and neuronal loss, akin to dopamine/carbidopa administration in DR mouse model. Conclusion Our findings unveil a pivotal role of CaMK2A/CREB signaling in driving mitophagy and neurodegeneration in DR. Targeting this pathway represents a potential therapeutic strategy for DR management.