Lee S Y, Oh J S, Rho J H, Jeong N Y, Kwon Y H, Jeong W J, Ryu W Y, Ahn H B, Park W C, Rho S H, Yoon Y G, Jeong S-Y, Choi Y H, Kim H Y, Yoo Y H
1] Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, South Korea [2] Department of Rheumatology, Dong-A University College of Medicine, Busan, South Korea.
1] Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, South Korea [2] Bong Seng Memorial Hospital, Busan, South Korea.
Cell Death Dis. 2014 Jun 26;5(6):e1303. doi: 10.1038/cddis.2014.266.
The increased mitochondrial DNA damage leads to altered functional capacities of retinal pigment epithelial (RPE) cells. A previous study showed the increased autophagy in RPE cells caused by low concentrations of rotenone, a selective inhibitor of mitochondrial complex I. However, the mechanism by which autophagy regulates RPE cell death is still unclear. In the present study, we examined the mechanism underlying the regulation of RPE cell death through the inhibition of mitochondrial complex I. We report herein that rotenone induced mitotic catastrophe (MC) in RPE cells. We further observed an increased level of autophagy in the RPE cells undergoing MC (RPE-MC cells). Importantly, autophagy inhibition induced nonapoptotic cell death in RPE-MC cells. These findings indicate that autophagy has a pivotal role in the survival of RPE-MC cells. We next observed PINK1 accumulation in the mitochondrial membrane and parkin translocation into the mitochondria from the cytosol in the rotenone-treated RPE-MC cells, which indicates that increased mitophagy accompanies MC in ARPE-19 cells. Noticeably, the mitophagy also contributed to the cytoprotection of RPE-MC cells. Although there might be a significant gap in the roles of autophagy and mitophagy in the RPE cells in vivo, our in vitro study suggests that autophagy and mitophagy presumably prevent the RPE-MC cells from plunging into cell death, resulting in the prevention of RPE cell loss.
线粒体DNA损伤增加会导致视网膜色素上皮（RPE）细胞的功能能力发生改变。先前的一项研究表明，线粒体复合物I的选择性抑制剂鱼藤酮的低浓度会导致RPE细胞中的自噬增加。然而，自噬调节RPE细胞死亡的机制仍不清楚。在本研究中，我们研究了通过抑制线粒体复合物I来调节RPE细胞死亡的潜在机制。我们在此报告，鱼藤酮在RPE细胞中诱导有丝分裂灾难（MC）。我们进一步观察到，经历MC的RPE细胞（RPE-MC细胞）中的自噬水平增加。重要的是，自噬抑制在RPE-MC细胞中诱导非凋亡性细胞死亡。这些发现表明，自噬在RPE-MC细胞的存活中起关键作用。接下来，我们观察到在鱼藤酮处理的RPE-MC细胞中，PINK1在线粒体膜上积累，并且parkin从细胞质易位到线粒体中，这表明在ARPE-19细胞中，MC伴随着线粒体自噬增加。值得注意的是，线粒体自噬也有助于RPE-MC细胞的细胞保护。尽管自噬和线粒体自噬在体内RPE细胞中的作用可能存在显著差异，但我们的体外研究表明，自噬和线粒体自噬可能会防止RPE-MC细胞陷入细胞死亡，从而防止RPE细胞丢失。
