Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes
Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes
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DOI：
10.1007/s12264-019-00459-5
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发表时间：
2020-01
影响因子：
5.6
通讯作者：
Cun-Jin Su;Zhu Shen;Ruicen Cui;Ya Huang;Delai Xu;Fenglun Zhao;Jie Pan;Aiming Shi;Tong Liu;Yun-Li Yu
中科院分区：
文献类型：
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作者：
Cun-Jin Su;Zhu Shen;Ruicen Cui;Ya Huang;Delai Xu;Fenglun Zhao;Jie Pan;Aiming Shi;Tong Liu;Yun-Li Yu
糖尿病患者患帕金森病（PD）的风险更高。然而，PD和糖尿病之间的分子联系仍不清楚。在这项研究中，我们研究了硫氧还蛋白相互作用蛋白（TXNIP）在高糖（HG）条件下多巴胺（DA）细胞中Parkin/PINK 1介导的线粒体自噬中的作用。在链脲佐菌素诱导的糖尿病小鼠中，TXNIP上调，自噬被抑制在中脑，而DA神经元的损失加速高血糖。在培养的PC 12细胞在HG，TXNIP表达上调，细胞内活性氧（ROS）水平增加，导致细胞死亡。HG条件下自噬通量进一步被阻断，PINK 1表达降低。HG还显著降低了线粒体组分中的Parkin表达和羰基氰化物3-氯苯腙（CCCP）诱导的考克斯IV（线粒体标记物）和LAMP 1（溶酶体标记物）的共定位。TXNIP的过表达足以降低PC 12细胞中PINK 1和Parkin的表达，而通过siRNA敲低TXNIP的表达降低了细胞内ROS，减轻了HG下的细胞损伤。此外，TXNIP的抑制增强CCCP诱导的考克斯IV和LAMP 1在HG下的PC 12细胞中的共定位。总之，这些结果表明，TXNIP调节Parkin/PINK 1介导的线粒体自噬在HG条件下，和靶向TXNIP可能是一个有前途的治疗策略，以降低高血糖条件下PD的风险。
Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.