Retinal pigment epithelial cells undergoing mitotic catastrophe are vulnerable to autophagy inhibition

Abstract

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.

Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium

“…In addition, cellular stressors in the eye, such as A2E accumulation, reactive oxygen species production and mitochondrial dysfunction can increase autophagy (20,21). Autophagic activity has also been observed to follow a cyclic pattern similar to the daily rhythm of POS phagocytosis detected in RPE cells; this suggests a role for autophagy in retinoid recycling and daily maintenance of photoreceptors (2,22).…”

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

“…In addition, the conversion of LC3 from LC3‐I to LC3‐II is a characteristic of autophagy . As indicated in Figure E, LC3‐II/LC3‐I ratio was increased in A549 and A549/Taxol cells in a time‐dependent manner after exposure to BZML.…”

“…Apoptosis has been a prevalent model in anti‐cancer drug development, but de‐regulated apoptotic signalling often leads to an increase of apoptosis resistance in cancer cells with the progression of treatment . Additionally, autophagy has been proposed as a tumour suppressor, plays a key pro‐survival role in cells by eliminating damaged organelles and proteins, and contributes apoptosis resistance in cancer cells . Importantly, the different functional forms of autophagy depend on the genetic background of cells, the microenvironment and the type of drug .…”

“…21,22 Additionally, autophagy has been proposed as a tumour suppressor, plays a key pro-survival role in cells by eliminating damaged organelles and proteins, and contributes apoptosis resistance in cancer cells. [23][24][25][26] Importantly, the different functional forms of autophagy depend on the genetic background of cells, the microenvironment and the type of drug. 27,28 Recently, other types of PCD, including necroptosis, MC and senescence, have been reported.…”

mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice

“…In the retinal pigment, epithelia, autophagy, and mitophagy (and most likely pexophagy and lysophagy) are cytoprotective functions linked mechanistically to protection against all- trans -retinal- and light-induced damage and photoreceptor cell death. 17,18 Results with trehalose, a nonreducing α-disaccharide, are particularly interesting because trehalose works in an mTOR-independent mechanism. 19,20 If regulation of autophagy is the primary mechanism through which rapalogs exert their efficacy through mTOR, trehalose could possess synergistic properties with mTOR inhibitors, including organelle stabilization and improved antioxidant status, while simultaneously reversing organelle proliferation.…”