Diabetic retinopathy (DR) is a major cause of vision loss in working-age adults with diabetes. Increasing evidence implicates neuroinflammation as a vital element in the disease process of DR, yet the molecular mechanisms by which neuroinflammation activation occurs are not fully understood. This study shows that elevated glucose levels enhance O-GlcNAcylation of voltage-dependent anion channel 1 (VDAC1) at threonine 165. This modification promotes VDAC1 oligomerization, facilitating cytosolic translocation of mtDNA. The cytosolic mtDNA activates Z-DNA binding protein 1, leading to its activation and subsequent inflammatory responses. Importantly, mtDNA levels in the vitreous fluid of patients with DR were higher, and mtDNA levels were positively correlated with the retinal thickness and negatively correlated with visual acuity. Taken together, our findings reveal a hyperglycemia-driven signaling axis in Müller cells that couples metabolic dysregulation with neuroinflammation, offering mechanistic insights and therapeutic opportunities for DR.
- The limited efficacy of anti-VEGF therapy in diabetic retinopathy (DR) highlights the importance of nonvascular mechanisms in disease progression.
- Hyperglycemia is a key driver of neuroinflammation in DR.
- Hyperglycemia results in VDAC1 O-GlcNAcylation in Müller glia, leading to mtDNA release and ZBP1 activation, thereby linking metabolic stress to neuroinflammation in DR.
- Targeting VDAC1-mediated mtDNA release or using vitreous mtDNA as a biomarker may enable earlier diagnosis and novel therapeutic strategies for DR.
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