Recurrent non-severe hypoglycemia (RH) in patients with diabetes might be associated with cognitive impairment. Previously, we found that mitochondrial dysfunction plays an important role in this pathological process; however, the mechanism remains unclear. The objective of this study was to determine the molecular mechanisms of mitochondrial damage associated with RH in diabetes mellitus (DM). We found that RH is associated with reduced hippocampal mitophagy in diabetic mice, mainly manifested by reduced autophagosome formation and impaired recognition of impaired mitochondria, mediated by the PINK1/Parkin pathway. The same impaired mitophagy initiation was observed in an in vitro high-glucose cultured astrocyte model with recurrent low-glucose interventions. Promoting autophagosome formation and activating PINK1/Parkin-mediated mitophagy protected mitochondrial function and cognitive function in mice. The results showed that impaired mitophagy is involved in the occurrence of mitochondrial dysfunction, mediating the neurological impairment associated with recurrent low glucose under high glucose conditions.

糖尿病患者复发性非严重低血糖（RH）可能与认知障碍有关。此前，我们发现线粒体功能障碍在这一病理过程中发挥着重要作用；然而，其机制仍不清楚。本研究的目的是确定糖尿病 (DM) 中与 RH 相关的线粒体损伤的分子机制。我们发现 RH 与糖尿病小鼠海马线粒体自噬减少有关，主要表现为自噬体形成减少和对受损线粒体的识别受损，由 PINK1/Parkin 通路介导。在体外高血糖培养的星形胶质细胞模型中观察到同样受损的线粒体自噬起始，并反复进行低血糖干预。促进自噬体形成并激活 PINK1/Parkin 介导的线粒体自噬可保护小鼠的线粒体功能和认知功能。结果表明，受损的线粒体自噬参与了线粒体功能障碍的发生，介导了高糖条件下与反复低糖相关的神经功能损伤。