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Activation of mitophagy improves cognitive dysfunction in diabetic mice with recurrent non-severe hypoglycemia
Kejun Wu1, Cuihua Huang1, Wenrong Zheng2
1Department of Endocrinology and Metabolism, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
Abstract:
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.
Insights
Recurrent hypoglycemia in diabetes impairs mitophagy, leading to mitochondrial damage and cognitive decline. Activating mitophagy pathways can restore mitochondrial and cognitive function.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Cellular Biology
Background:
- Recurrent non-severe hypoglycemia (RH) in diabetes mellitus (DM) is linked to cognitive impairment.
- Mitochondrial dysfunction is implicated, but the precise mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of mitochondrial damage in the context of RH in DM.
- To investigate the role of mitophagy in RH-associated neurological deficits.
Main Methods:
- Utilized diabetic mouse models and in vitro astrocyte cultures subjected to high-glucose and recurrent low-glucose conditions.
- Examined hippocampal mitophagy, focusing on autophagosome formation and mitochondrial recognition via the PINK1/Parkin pathway.
Main Results:
- RH was associated with reduced hippocampal mitophagy in diabetic mice, characterized by impaired autophagosome formation and mitochondrial clearance.
- Impaired mitophagy initiation was replicated in vitro, implicating the PINK1/Parkin pathway.
- Enhancing mitophagy improved mitochondrial and cognitive function in mice.
Conclusions:
- Impaired mitophagy is a key factor in RH-induced mitochondrial dysfunction and subsequent neurological impairment in diabetes.
- The PINK1/Parkin pathway is central to the observed mitophagy deficits.
- Targeting mitophagy presents a potential therapeutic strategy for cognitive dysfunction in diabetic patients experiencing recurrent hypoglycemia.
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