GPR75 knockdown alleviates mitochondrial dysfunction in retinal ganglion cells via AMPK pathway in diabetic mice.

Mitochondrial dysfunction plays a crucial role in retinal ganglion cells (RGCs) injury, the early pathogenesis of diabetic retinopathy (DR). G protein-coupled receptor 75 (GPR75), an orphan receptor, is a novel regulator of metabolic diseases. However, the role and mechanisms of GPR75 underlying diabetic RGCs mitochondrial dysfunction have not been reported. To investigate the function of GPR75, we knockdown the receptor in streptozotocin (STZ) mice and high glucose (HG)-treated primary RGCs. Our investigations revealed an upregulation of GPR75 in DR. Furthermore, we demonstrated that GPR75 knockdown could mitigate the progression of DR, with its protective effects associated with the inhibition of mitochondrial dysfunction in RGCs. Adenosine-5'-monophosphate (AMP)-activated protein kinase (AMPK), a regulator of mitochondrial function and a cellular energy sensor, was identified as a novel target of GPR75. Immunofluorescence and co-immunoprecipitation (CO-IP) analyses confirmed the co-localization and interaction between GPR75 and AMPK in RGCs. Mechanistically, the upregulation of GPR75 inhibits AMPK-mediated mitochondrial homeostasis, resulting in impaired mitochondrial dynamics, disrupted energy metabolism, and elevated reactive oxygen species (ROS), which ultimately trigger pyroptosis and apoptosis in RGCs. Notably, the AMPK-activator AICAR mitigates GPR75-induced mitochondrial dysfunction, pyroptosis, and apoptosis. In summary, our findings suggest that the targeted inhibition of GPR75 may represent a promising therapeutic strategy for DR.