GPR75 knockdown alleviates mitochondrial dysfunction in hippocampal neurons via AMPK pathway in diabetic mice

Diabetic cognitive dysfunction (DCD) is widely acknowledged as a cerebral complication of diabetes mellitus involving hippocampal neuronal damage caused by mitochondrial dysfunction. G protein-coupled receptor 75 (GPR75) is an Orphan Receptor associated with inflammation, mitochondrial function, and metabolic disorders. However, its exact role in DCD has not yet been reported. In order to investigate the effect of GPR75 on DCD, we employed streptozotocin (STZ)-treated C57BL/6 J mice and high glucose (HG)-treated mouse hippocampal neuronal cells (HT22). Our investigations revealed upregulation of GPR75 in DCD. Furthermore, we demonstrated that knocking down GPR75 could mitigate the progression of DCD, with its protective effects associated with the inhibition of mitochondrial dysfunction in hippocampal neurons. AMP-activated protein kinase (AMPK), a regulator of mitochondrial function and cellular energy sensor, was identified as a novel target for GPR75. Immunofluorescence and co-immunoprecipitation (CO-IP) analyses confirmed the co-localization and interaction between GPR75 and AMPK in HT22 cells. 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 triggers Pyroptosis and Apoptosis in hippocampal neurons. Notably, the AMPK-activator AICAR mitigates GPR75-induced mitochondrial dysfunction, Pyroptosis, and Apoptosis. In summary, our findings suggest that targeted inhibition of GPR75 may represent a promising therapeutic strategy for DCD.

AMPK; Diabetic cognitive dysfunction; GPR75; Hippocampal neurons; Mitochondrial dysfunction.