Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway.

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.