OGT Ameliorates Diabetes-Associated Cognitive Decline via Modulation of DRP1 Function and Mitochondrial Homeostasis

Diabetes-associated cognitive decline (DACD) is gradually gaining attention as a major complication of diabetes. However, to date, the specific molecular mechanisms underlying DACD have not been thoroughly characterized.

Db/db and streptozotocin (STZ) treated high-fat diet (HFD)-induced mice were established. Different behavioural assessments were performed, followed by evaluation of mitochondrial homeostasis, including mitochondrial morphology and function. Mitochondrial dynamics proteins, synaptic-related proteins and O-GlcNAc cycling enzymes were examined. Thereafter, OGT-interacting proteins were identified using co-immunoprecipitation mass spectrometry. Additionally, mouse hippocampal neuronal cells were treated with OGT siRNA and subsequent changes were measured. Mice were stereotaxically injected with adeno-associated viruses to overexpress OGT specifically in the hippocampus, and relevant in vivo experiments were performed. Finally, mice received semaglutide for 16 weeks and subsequent changes were assessed.

Decreased OGT expression disrupted mitochondrial homeostasis and led to neuronal injury and cognitive impairment in diabetic mice. In addition, hippocampus-specific OGT overexpression improved DACD. Mechanistically, OGT deficiency resulted in a reduced mitochondrial membrane potential, promoting mitochondrial fission and impairing mitochondrial function by modulating DRP1 function. Furthermore, our results showed that semaglutide alleviated DACD through the OGT/DRP1 pathway.

OGT deficiency-mediated mitochondrial homeostasis imbalance contributes to the occurrence of DACD, and semaglutide with an OGT protective effect may be a potential therapeutic approach for DACD.