Maintaining blood sugar level is critical for the management of patients with diabetes. However, accidental recurrent excessive low blood sugar – hypoglycemia induced by insulin is associated with neural damage and cognitive impairment (Freeman, 2019; Nilsson et al., 2019; Sheen and Sheu, 2016). In addition to severe hypoglycemia, which can cause life threatening events, patients frequently experience non-severe hypoglycemia, which normally causes mild discomfort at the time of attack. Therefore, non-severe hypoglycemia is often neglected by patients, leading to recurrent hypoglycemia (Cariou et al., 2015). However, the accumulative damage from recurrent non-severe hypoglycemia can lead to increased cognitive impairment (Barbagallo and Dominguez, 2014; Gao et al., 2021; Zhou et al., 2018), cardiovascular disease, and all-cause mortality (Luk et al., 2016). The mechanisms of neural damage induced by recurrent hypoglycemia involve fuel supply disturbance, oxidative stress, and synaptic damage (McNay and Cotero, 2010).

Neurons require high energy levels to maintain their functions. Their energy support is provided by astrocytes (Chen et al., 2022), the most abundant glial cells in the brain. The main functions of astrocytes include providing energy support for neurons, regulating glutamate-glutamine circulation, secreting neurotrophic factors, and regulating the number and function of synapses (Douglass et al., 2017; Mason, 2017). In particular, astrocytes receive damaged mitochondria from neurons for degradation and regeneration, and deliver healthy mitochondria to neurons to assist them in defending against various injuries (Hayakawa et al., 2016). Pathological damage, including diabetic hypoglycemia-associated glucose deprivation, impairs the functions of astrocytes, leading to disturbed neuronal support, resulting in neuronal injury and death (Pekny et al., 2016). Mitochondrial dysfunction in astrocytes is involved in the pathophysiological process of cognitive disorders (Gollihue and Norris, 2020; Kuchibhotla et al., 2009). Our published studies have shown that recurrent hypoglycemia causes neural damage and cognitive impairment in mice by impairing mitochondrial structure and function; in particular, impaired mitochondrial function leads to astrocyte damage and decreased secretion of neurotrophic factors, thereby aggravating neuronal injury (Zhou et al., 2018; Gao et al., 2021). However, the specific mechanism of mitochondrial dysfunction in this process remains unclear.

Mitophagy is a process of selective autophagy in cells, which plays a role in maintaining the quantity and quality of normal mitochondria and protects mitochondrial function through the selective degradation of damaged mitochondria (Ding and Yin, 2012). The process of mitophagy includes the recognition of damaged mitochondria, autophagosome generation, damaged mitochondria phagocytosis and mitophagosome formation, lysosome fusion with the mitophagosome, and the degradation of damaged mitochondria (Kerr et al., 2017). The identification of damaged mitochondria mainly relies on the PTEN-induced putative kinase 1 (PINK1)-Parkin pathway (Yang et al., 2020), which is involved in the initiation of mitophagy together with autophagosome generation. Defective mitophagy leads to the accumulation of damaged mitochondria and increased reactive oxygen species (ROS), resulting in cell damage, while excessive mitophagy results in the division of healthy mitochondria, leading to cell death (Su et al., 2018). It has been reported that mitochondrial dysfunction caused by impaired mitophagy affects the ability of astrocytes to support neurons (Ren et al., 2020). However, no study has examined the role of astrocyte mitophagy abnormalities in hypoglycemia-related cognitive impairment.

Therefore, we conducted this study to investigate the role of mitophagy in cognitive impairment caused by recurrent non-severe hypoglycemia in diabetes. In addition, we continue our previous research to explore the effect of regulating mitophagy on mitochondrial function based on astrocytes.