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Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway
Siyu Lin1, Zhiyu Ji1, Jie Gao1
1Department of Ophthalmology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
Background And Aim:
Inflammation is a crucial aspect of the pathophysiology of diabetic retinopathy (DR). Polymerase delta-interacting protein 2 (Poldip2) has been linked to inflammation in various disorders, but its role in DR remains unclear. This study aims to elucidate the underlying mechanisms of Poldip2 in DR.
Methods:
Transmission Electron Microscopy (TEM) revealed significant mitophagy reduction due to the accumulation of damaged mitochondria in the retinas of Streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rats. In vivo, AAV9-Poldip2-shRNA was administered to STZ-induced DR rats, partially restoring mitophagy. Microglia (BV2) cells cultured in high glucose (HG) conditions exhibited similar behavior. Likewise, BV2 received Poldip2-siRNA treatment to further explore the regulatory mechanism of Poldip2.
Results:
In vivo, Poldip2 was significantly elevated alongside VEGFR and SQSTM1/P62, while mitophagy markers were inhibited. Under HG conditions, BV2 secret large amounts of pro-inflammatory factors. Human Retinal Microvascular Endothelial Cells (HRMECs) were significantly affected by these HG-cultured BV2, leading to angiogenesis. Notably, Poldip2 knockdown significantly increased Pink1 by preventing its ubiquitination-mediated degradation, thereby enhancing mitophagy and reducing retinal inflammation.
Conclusion:
Our findings suggest that Poldip2 contributes to DR by promoting Pink1 degradation, which inhibits mitophagy and leads to inflammation. Targeting Poldip2 may offer a novel therapeutic strategy for DR.
Insights
Polymerase delta-interacting protein 2 (Poldip2) inhibition reduces inflammation in diabetic retinopathy (DR) by enhancing mitophagy and preventing Pink1 degradation. Targeting Poldip2 may offer a novel therapeutic strategy for DR.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Medicine
Background:
- Diabetic retinopathy (DR) involves significant inflammation.
- The role of Polymerase delta-interacting protein 2 (Poldip2) in DR pathogenesis is not well understood.
- Poldip2 is implicated in inflammation in other diseases.
Purpose of the Study:
- To investigate the role and mechanism of Poldip2 in diabetic retinopathy.
- To elucidate how Poldip2 influences mitophagy and inflammation in the retina.
Main Methods:
- Utilized Streptozotocin (STZ)-induced diabetic rats and high glucose (HG) cultured microglia (BV2) and human retinal microvascular endothelial cells (HRMECs).
- Administered AAV9-Poldip2-shRNA in vivo and Poldip2-siRNA in vitro.
- Assessed mitophagy, mitochondrial damage, pro-inflammatory factors, angiogenesis, and Pink1 ubiquitination via Transmission Electron Microscopy (TEM) and molecular assays.
Main Results:
- STZ-induced diabetic rats showed reduced mitophagy and elevated Poldip2, VEGFR, and SQSTM1/P62.
- HG-induced BV2 cells secreted pro-inflammatory factors, affecting HRMECs and promoting angiogenesis.
- Poldip2 knockdown enhanced mitophagy by increasing Pink1 levels (preventing degradation) and reduced retinal inflammation.
Conclusions:
- Poldip2 exacerbates DR by inhibiting mitophagy through promoting Pink1 degradation, leading to retinal inflammation.
- Targeting Poldip2 presents a potential therapeutic avenue for managing diabetic retinopathy.
