Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E

Saadat, Khandakar A.S.M.; Murakami, Yusuke; Tan, Xue; Nomura, Yoko; Yasukawa, Tsutomu; Okada, Eiichi; Ikeda, Yasuhiro; Yanagi, Yasuo

doi:10.1016/j.fob.2014.11.003

Cited by 40 publications

(29 citation statements)

References 39 publications

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“…A study by Saadat et al observed that blocking autophagy greatly increased A2E-induced cell death in ARPE-19 cells (20). Interestingly, genes involved in both autophagy and apoptosis such as CASP3, DRAM1 and PERK were up-regulated after A2E incubation in our gene array.…”

Section: Discussionmentioning

confidence: 49%

“…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).…”

Section: Autophagy Is An Evolutionarily Conserved Catabolic Mechanismmentioning

confidence: 86%

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

Perusek¹,

Sahu²,

Parmar³

et al. 2015

Journal of Biological Chemistry

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Background: Atg7 is an essential autophagic enzyme. Disrupted autophagy has been implicated in retinal degeneration. Results: Mice with RPE-specific Atg7 deletion exhibit normal retinoid recycling, histology, and A2E accumulation, but display hypertrophy and cytosolic debris. Conclusion: Atg7 deficiency does not severely affect the health of RPE cells in mice. Significance: A2E accumulation and retinoid recycling are independent of Atg7-mediated autophagy in RPE cells.

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Section: Discussionmentioning

confidence: 49%

Section: Autophagy Is An Evolutionarily Conserved Catabolic Mechanismmentioning

confidence: 86%

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

Perusek¹,

Sahu²,

Parmar³

et al. 2015

Journal of Biological Chemistry

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“…This is consistent with Janet R. Sparrow's research [29,30] and close to the research on human donors' eyes [31] . In recent years, a lot of research has proved that A2E not only induces the photodamage of RPE cells [32][33][34][35] , but also causes inflammation [36][37][38][39] , and these are the major risk factors of retinal degenerative disease. Therefore, the blue light-induced A2E-containing RPE cell damage model we have established is a proper in vitro model for investigating the pathological changes of retinal degenerative disease.…”

Section: Discussionmentioning

confidence: 99%

Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

Zhang

Zhou

et al. 2017

Ophthalmic Res

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Purpose: Retinal pigment epithelium (RPE) cell dysfunction is essential to the development of retinal degenerative disease. This study was designed to investigate how spliced X-box-binding protein 1 (XBP1s) regulates different modes of RPE cell death in vitro. Methods: Human ARPE19 cells were incubated with 25 μM N-retinylidene-N-retinylethanolamine (A2E) and irradiated with blue light. Expressions of glucose-regulated protein 78 (GRP78) and XBP1s were detected by real-time quantitative PCR and Western blot. STF-083010 was used to suppress XBP1s expression. ARPE19 cell apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry. Receptor-interacting protein kinase-3 (RIP3) was detected by Western blot. Changes in the morphology of ARPE19 cells were identified by transmission electron microscopy. Results: Blue light-induced A2E-containing ARPE19 cell damage caused a transient elevation of GRP78 and XBP1s, while RIP3 rose in the late stage. STF-083010 effectively inhibited XBP1s expression and brought about the aggravation of apoptosis together with an alleviation of RIP3 expression. Most of the dying cells exhibited apoptotic morphology. Conclusion: A2E, along with blue light, brought about apoptosis and necroptosis of ARPE19 cells, and XBP1s was transiently elevated. The suppression of XBP1s induced ARPE19 cell death by promoting apoptosis rather than necroptosis. XBP1s might play a role in the pathogenesis of retinal degenerative diseases.

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“…In vivo deletion of autophagic gene RB1CC1 in mouse retina results in retinal degeneration that shares many features with AMD disease [109]. RPE cells in vitro accumulate lipofuscin and greater loss of mitochondrial activity and membrane integrity under oxidative stress when autophagy is inhibited [13,125,203]. Autofluorescent lipofuscin in the RPE destabilizes the lysosome and is a hallmark of RPE senescence that has been widely implicated in AMD [204,205].…”

Section: Retinamentioning

confidence: 99%

“…Autophagy plays a critical role in controlling NLRP3 inflammasome activity in the retina. Several in vitro experiments show dramatic upregulation of inflammasome activity in RPE and secretion of IL-1β after autophagic flux inhibition [139][140][141] [203]. Wortmannin inhibits autophagy by inhibiting class III PI3Kinase [241].…”

Section: Non-canonical Lc3 Associatedmentioning

confidence: 99%

Autophagy in Ocular Pathophysiology

Mitter¹,

Boulton²

2016

Autophagy in Current Trends in Cellular Physiology and Pathology

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Autophagy is an evolutionarily conserved intracellular recycling pathway that is indispensable for cellular quality control. Dysfunctional autophagy has been associated with several neurodegenerative, myodegenerative, infectious, and cancerous disorders. Autophagic processes are not only important for cellular maintenance in the retina but also intimately involved with phagocytosis and the very core of retinal visual process. Additionally, excessively upregulated autophagy may culminate into a cell death modality, which may be detrimental to the non-dividing cells of various eye segments. Major advances have been made in understanding the role and fate of autophagy in different ocular tissue layers. In this chapter, we summarize the current understanding of autophagy in the eye in the context of development, aging, and disease. We also speculate on the putative therapeutic strategies where autophagy may be incorporated to treat oculopathies.

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Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E

Cited by 40 publications

References 39 publications

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

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

Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

Autophagy in Ocular Pathophysiology

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