Autophagy, lysosome dysfunction and mTOR inhibition in MNU-induced photoreceptor cell damage

Liu, Ying; Wang, Chenguang; Liu, Yang; You, Jiaxin; Su, Guanfang

doi:10.1016/j.tice.2019.09.008

Cited by 13 publications

(14 citation statements)

References 55 publications

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“…However, when damage is severe, autophagy can lead to apoptotic cell death; indeed, many regulators of autophagy pathways also have central roles in regulating apoptosis [ 34 ]. Autophagy has been associated with photoreceptor death in RP models in many different studies [ 35 , 36 , 37 , 38 ], but the precise role of this pathway remains controversial. As discussed later in this review, increased autophagy flux (the dynamic process of autophagy) appears to be protective in some animal models of RP while other studies have suggested autophagy reduces photoreceptor survival [ 22 , 35 , 36 ].…”

Section: Cell Death Mechanismsmentioning

confidence: 99%

“…Phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K/Akt pathway, was up-regulated in rd10 photoreceptors and the authors also showed that cell-specific deletion of PTEN reduced apoptosis of photoreceptors in rd10 mice, leading to enhanced visual function. Further, inhibition of the PI3K/mTOR pathway has also been observed in MNU damaged photoreceptors in culture, leading to the activation of autophagy [ 38 ]. Prolonged autophagy activation resulted in the accumulation of autophagic vacuoles, indicated by enlarged lysosomes, and ultimately led to cell death by apoptosis.…”

Section: Pathways Leading To the Death Of Rod Photoreceptors In Rpmentioning

confidence: 99%

“…Conversely, autophagy may have a protective function in the early stages of photoreceptor degeneration when other genes are involved, with other cell death mechanisms becoming up-regulated in later stages of RP as damage becomes more severe. For example, whilst autophagy is up-regulated in MNU-damaged photoreceptors in vitro, inhibition of autophagosome formation in these cells with 3-methyladenine accelerates cell damage and apoptosis [ 38 ]. Conversely, these authors found that prolonged activation of autophagy in MNU-damaged cells resulted in the accumulation of autophagic vacuoles, eventually leading to cell death by apoptosis.…”

Section: Pathways Leading To the Death Of Rod Photoreceptors In Rpmentioning

confidence: 99%

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Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

146

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Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

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Section: Cell Death Mechanismsmentioning

confidence: 99%

Section: Pathways Leading To the Death Of Rod Photoreceptors In Rpmentioning

confidence: 99%

Section: Pathways Leading To the Death Of Rod Photoreceptors In Rpmentioning

confidence: 99%

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Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

146

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“…These are regarded as reliable autophagy markers. Several studies have shown that promoting autophagy through various signaling pathways, such as the PI3K/protein kinase B (Akt)/mTOR pathway [ 76 , 77 ], the AMPK/mTOR pathway [ 38 ], the p62/Kelch-like-ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (NFE2L2) pathway, and the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) pathway [ 78 , 79 ], could reduce the occurrence of AMD. The levels of Beclin-1 and the ratio of LC3-II to LC3-I (LC3-II/LC-I) were found to be increased in these studies.…”

Section: The Role Of Autophagy In Amdmentioning

confidence: 99%

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

Zhang

Bao

Cong

et al. 2020

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD) is a leading cause of severe visual loss and irreversible blindness in the elderly population worldwide. Retinal pigment epithelial (RPE) cells are the major site of pathological alterations in AMD. They are responsible for the phagocytosis of shed photoreceptor outer segments (POSs) and clearance of cellular waste under physiological conditions. Age-related, cumulative oxidative stimuli contribute to the pathogenesis of AMD. Excessive oxidative stress induces RPE cell degeneration and incomplete digestion of POSs, leading to the continuous accumulation of cellular waste (such as lipofuscin). Autophagy is a major system of degradation of damaged or unnecessary proteins. However, degenerative RPE cells in AMD patients cannot perform autophagy sufficiently to resist oxidative damage. Increasing evidence supports the idea that enhancing the autophagic process can properly alleviate oxidative injury in AMD and protect RPE and photoreceptor cells from degeneration and death, although overactivated autophagy may lead to cell death at early stages of retinal degenerative diseases. The crosstalk among the NFE2L2, PGC-1, p62, AMPK, and PI3K/Akt/mTOR pathways may play a crucial role in improving disturbed autophagy and mitigating the progression of AMD. In this review, we discuss how autophagy prevents oxidative damage in AMD, summarize potential neuroprotective strategies for therapeutic interventions, and provide an overview of these neuroprotective mechanisms.

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“…Apoptosis and autophagy are mediated by multiple signaling pathways, among which mTOR signaling pathway is the most important ( 26 , 27 ). It has been reported that ANXA2 can regulate autophagy in Pseudomonas aeruginosa infection through the AKT1-mTOR-ULK1/2 signaling pathway ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Effect and mechanism of action of SLP‑2 on the apoptosis and autophagy of gastric cancer cells

et al. 2021

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This study was designed to investigate the effect of stomatin-like protein 2 (SLP-2) on the apoptosis and autophagy of gastric cancer cells and its underlying mechanism. The expression of SLP-2 was detected in human gastric cancer cell lines (AGS, MKN-45 and NCI-N87) and a human gastric epithelial cell line (GES-1) using reverse transcription-quantitative PCR and western blot analysis. SLP-2-specific small interfering RNA (siRNA) was transfected into NCI-N87 cells. Cell Counting Kit-8 was used to detect cell proliferation. Apoptosis rates were measured using flow cytometry. Autophagosomes were observed by transmission electron microscopy. The expression levels of Annexin A2 (ANXA2), β-catenin, Bcl-2, Bax, Beclin-1 and LC3-II/I were also measured. The results demonstrated that SLP-2 siRNA transfection significantly reduced cell proliferation and increased cell apoptosis. The mitochondria were severely damaged, and a large number of autophagosomes were seen in SLP-2 siRNA-transfected NCI-N87 cells. Furthermore, the expression levels of ANXA2, β-catenin and Bcl-2 were downregulated, whereas those of Bax, Beclin-1 and LC3-II/I were upregulated following SLP-2 siRNA transfection. In conclusion, SLP-2 silencing can inhibit proliferation and induce apoptosis and autophagy of gastric cancer cells, and this effect may be related to the inhibition of ANXA2/β-catenin signaling pathway.

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Autophagy, lysosome dysfunction and mTOR inhibition in MNU-induced photoreceptor cell damage

Cited by 13 publications

References 55 publications

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

Effect and mechanism of action of SLP‑2 on the apoptosis and autophagy of gastric cancer cells

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