Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Abstract

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

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

“…However, the upstream regulatory molecule for Mff-required mitochondrial fission in the setting of DN remains unknown. In response to mitochondrial fission, mitochondria could employ lysosomes via Parkin to degrade damaged mitochondria and maintain a healthy mitochondrial population, which is essential for cell survival [18][19][20]. Notably, the impairment of Parkin-mediated mitophagy is a feature of DN, and various pharmacological activators of mitophagy have been shown to protect against glomerulosclerosis and proteinuria, renal hypertrophy, and mesangial expansion in rodent DN models [21][22][23].…”

Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways

“…Mammalian STE20-like kinase 1 (Mst1) is an element of the Hippo pathway, which was initially identified as a major growth suppressor that interrupts stem cell growth, proliferation and apoptosis ( 3 ). Subsequent studies have illustrated that Mst1 is also involved in sustaining cardiomyocyte survival in diabetic cardiomyopathy ( 4 , 5 ), suppressing endometrial stromal cell migration in endometriosis ( 6 ) and promoting cancer cell apoptosis in colorectal carcinoma ( 7 ). These findings indicated that Mst1 functions as a tumor suppressor by modulating cancer cell apoptosis, migration and proliferation.…”

Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways

“…Notably, various pathways seem to be involved in the pathological process of different diseases. For example, in the models of cardiac ischemia reperfusion injury [ 32 ] and endometriosis metastasis [ 33 ], the JNK-Mff pathway is activated and contributes to the augmentation of mitochondrial fission and cardiomyocyte death. In contrast, in cerebral ischemia reperfusion injury and hyperglycemia-mediated renal damage, mitochondrial fission is primarily activated by the ROCK1-Drp1 pathways [ 31 ].…”