In the present study, our data showed that (1) T2DM induced excessive mitochondrial fission and suppressed mitophagy in the hippocampus; (2) cav-1 overexpression conferred substantial protective effects against DACD by preserving mitochondrial fission-mitophagy axis; (3) GSK3β/Drp1 signaling served as a novel down-stream target of mitochondrial fission inhibition by cav-1; (4) the interaction between cav-1 and AMPK is the key for cav-1 to promote mitophagy during T2DM. The gene discussed is GSK3B; the disease is type 2 diabetes mellitus.