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首页> 外文期刊>Cellular Physiology and Biochemistry >Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy
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Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

机译：Mst1对子宫内膜异位症细胞凋亡和迁移的影响：与Drp1相关的线粒体裂变和帕金所需的线粒体的作用。

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Background/Aims Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular oxidative stress, energy metabolism and calcium overload. Through excessive mitochondrial fission and aberrant mitophagy, Mst1 launched caspase 9-related mitochondrial apoptosis and abrogated F-actin/lamellipodium-dependent cellular migration. Notably, we also defined NR4A/miR181c as the upstream signal for Mst1 dysfunction in endometriosis. Conclusion Collectively, our results comprehensively described the important role of the NR4A-miR181c-Mst1 pathway in endometriosis, which handled mitochondrial apoptosis and F-actin/ lamellipodium-based migration via the regulation of Drp1-related mitochondrial fission and Parkin-required mitophagy, with a potential application in endometriosis therapy by limiting ESCs migration and promoting apoptosis.
机译：背景/目的线粒体内稳态通过定义不明确的机制参与子宫内膜异位症的发生和发展。 Mst1是与癌症迁移，凋亡和增殖有关的主要生长抑制剂。但是，Mst1是否通过调节线粒体功能参与子宫内膜异位症的凋亡和迁移尚待阐明。方法通过蛋白质印迹法检测子宫内膜异位症中Mst1的表达。通过MTT和TUNEL测定法检测细胞凋亡。通过腺病毒过表达进行关于Mst1的功能测定。通过线粒体膜电位JC-1染色，ROS流式细胞术分析，mPTP开放性评估和HtrA2 / Omi的免疫荧光评估线粒体功能。通过western印迹和免疫荧光检查线粒体的活性。结果首先，我们发现子宫内膜异位症异位内膜中的Mst1与正常子宫内膜相比显着下调。但是，Mst1功能的恢复与子宫内膜基质细胞（ESC）不能迁移和存活密切相关。一项功能研究表明，重新获得Mst1可以增强Ser616处的Drp1转录后磷酸化，并通过p53抑制Parkin转录活性，从而导致线粒体裂变激活和线粒体抑制。与Drp1相关的过度裂变迫使线粒体将HtrA2 / Omi释放到细胞质中。此外，Mst1诱导的缺陷型吞噬引起细胞氧化应激，能量代谢和钙超载。通过过度的线粒体裂变和异常的线粒体吞噬，Mst1启动了与胱天蛋白酶9相关的线粒体凋亡，并废除了依赖F-肌动蛋白/ lamellipodium的细胞迁移。值得注意的是，我们还将NR4A / miR181c定义为子宫内膜异位症Mst1功能障碍的上游信号。结论总体而言，我们的结果全面描述了NR4A-miR181c-Mst1途径在子宫内膜异位症中的重要作用，该途径通过调节Drp1相关的线粒体裂变和帕金所需的线粒体吞噬作用来处理线粒体凋亡和F-肌动蛋白/薄片状脂质体迁移。通过限制ESC迁移并促进细胞凋亡在子宫内膜异位症治疗中的潜在应用。

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