CaMK2A/CREB pathway activation is associated with enhanced mitophagy and neuronal apoptosis in diabetic retinopathy

Area of Science:

• Ophthalmology
• Neuroscience
• Cell Biology

Background:

• Diabetic retinopathy (DR) is a leading cause of vision impairment due to diabetes mellitus.
• The Ca2+/calmodulin-dependent protein kinase II alpha (CaMK2A) and cAMP response element-binding protein (CREB) pathway is implicated in neurological disorders, but its role in DR is unclear.
• Mitophagy, a selective form of autophagy, is increasingly recognized in neurodegenerative diseases.

Purpose of the Study:

• To investigate the role of the CaMK2A/CREB signaling pathway in diabetic retinopathy (DR) pathogenesis.
• To explore the interplay between CaMK2A/CREB signaling and mitophagy in DR.
• To evaluate the therapeutic potential of targeting CaMK2A/CREB and mitophagy in DR.

Main Methods:

• Established a streptozotocin-induced DR mouse model and used in vitro high-glucose (HG) treatment on primary mouse retinal ganglion cells.
• Conducted histological, biochemical, and molecular analyses, including CaMK2A/CREB pathway assessment and mitophagy evaluation.
• Employed pharmacological and genetic interventions targeting CaMK2A/CREB and mitophagy.

Main Results:

• DR model and HG treatment showed retinal degeneration, apoptosis, neurotransmitter depletion, enhanced mitophagy, and CaMK2A/CREB pathway activation.
• Autophagy inhibition partially rescued cell death but did not affect CaMK2A/CREB activation, indicating mitophagy is downstream.
• CaMK2A inhibition or CREB phosphorylation blockade attenuated HG-induced mitophagy and apoptosis; CaMK2A silencing improved DR outcomes.

Conclusions:

• CaMK2A/CREB pathway activation and enhanced mitophagy are key events in diabetic retinopathy (DR) pathogenesis.
• Mitophagy is a downstream consequence of CaMK2A/CREB activation in DR.
• Targeting the CaMK2A/CREB pathway and mitophagy presents a promising therapeutic strategy for managing DR.