Metformin Ameliorates Diabetes-Associated Cognitive Dysfunction via p53/Parkin-Mediated Mitophagy

Diabetes-associated cognitive dysfunction (DACD) is a common and serious diabetic complication, and emerging evidence has identified impaired mitophagy as its potential pathological feature. Metformin (Met) possesses both hypoglycemic and cognitive-enhancing activities, and also exerts modulatory effects on mitophagy. However, the precise mechanisms by which it regulates mitophagy to ameliorate DACD remain poorly understood.

Our present study aims to verify the ameliorative effects of Met on cognitive dysfunction in DACD mice, and to explore its underlying mechanisms.

Cognitive function of type 2 diabetes mellitus (T2DM) mice was evaluated by behavioural tests after Met administration. Proteomic profiling and multiple molecular biology techniques were utilised to explore and validate the effect of Met on mitophagy in T2DM mice, as well as in high glucose (HG)-injured HT22 and SH-SY5Y cells.

We found that Met significantly alleviated cognitive impairment and neuronal damage in T2DM mice. Proteomic analysis indicated that the effect of Met in improving cognition might be closely related to mitophagy regulation. Furthermore, Met markedly downregulated Beclin1, Atg4, Atg7, LC3 II, PINK1, and Parkin in the hippocampus of T2DM mice, while upregulating p62 levels. Simultaneously, Met reduced the colocalisation of mitochondria and autophagosome marker LC3B, and the colocalisation of mitochondria and lysosome. These results indicated that Met could reverse excessive mitophagy activation. Moreover, Met dramatically increased the cytoplasmic expression of p53 and Parkin, while inhibiting the translocation of Parkin to damaged mitochondria. Consistent results were also observed in HG-injured HT22 and SH-SY5Y cells after Met incubation. Notably, the effect of Met on mitophagy and p53 was blocked by the p53 inhibitor PFT-α.

Our study confirmed that Met inhibited the mitochondrial localisation of Parkin by elevating cytosolic p53 levels, thereby preventing excessive mitophagy and ameliorating DACD.

These findings indicated that Met might have potential for clinical repurposing in the treatment of DACD.