萜品烯-4-醇通过Parkin/MCU通路恢复线粒体自噬抑制β细胞去分化的机制

Abstract

Background and Objective Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised by insulin resistance and β-cell impairment. Dedifferentiation of pancreatic β-cells contributes to the progression of T2DM, influencing insulin secretion through mechanisms such as mitochondrial dysfunction, Ca 2+ overload and impaired autophagy. This study investigated the effects of terpinen-4-ol (T4O) on β-cell dedifferentiation and mitochondrial autophagy, with an emphasis on the role of the Parkin/MCU signalling pathway. Methods A T2DM mouse model was generated using a high-fat diet (HFD, 60% fat) and STZ (50 mg/kg) injection, and β-cell dedifferentiation was induced by high glucose (HG) treatment in MIN6 cells. T4O was administered, and its effects on mitochondrial autophagy and β-cell dedifferentiation were evaluated. The mitochondrial autophagy agonist NMN and the MCU inhibitor RU360 were used to assess the interplay between mitophagy and Ca 2+ signalling. Parkin was overexpressed in vitro and in vivo to determine its contribution to mitochondrial autophagy and Ca 2+ regulation. The investigation of the mechanism of the Parkin/MCU signalling pathway involved co-immunoprecipitation (Co-IP), mass spectrometry (MS) and protein synthesis inhibition assays. Results T4O improved blood glucose levels and insulin resistance in diabetic mice. In vitro and in vivo, T4O reduced the expression of dedifferentiation markers (such as OCT4, MafA and Pdx1 and Ngn3), increased the expression of mitochondrial autophagy-related proteins (PINK1, Parkin, Beclin and LC3-II/I) and modulated the expression of MCU and Drp1 (downregulated) as well as MFN2 (upregulated). T4O also alleviated HG-induced mitochondrial damage, including ultrastructural abnormalities, decreased membrane potential, elevated reactive oxygen species and Ca 2+ overload. In addition, preincubation of MIN6 cells with T4O or the mitochondrial autophagy agonist NMN can reduce HG-induced mitochondrial Ca 2+ overload, pro