Autophagy is a lysosomal degradation process that maintains cellular homeostasis by removing dysfunctional organelles and unfolded proteins. Increasing evidence has shown that autophagy proteins are involved in retinal physiology and pathology and that defective autophagy contributes to retinal degeneration. In retinal diseases, autophagy plays a dual role: promoting retinal cell survival and death. Autophagy at a normal level helps retinal cells defend themselves against harmful stress; however, excessive autophagy results in retinal deterioration. Both synergistic and antagonistic roles of autophagy and apoptosis in the retina have been reported in the literature. In this review, we summarize the roles of autophagy in the development of the retina and retinal diseases. This review highlights the importance of autophagy in retinal diseases, and targeting autophagy may provide a new therapeutic approach for retinal diseases.

Autophagy is an evolutionarily conserved degradation process that mediates intracellular degradation of damaged organelles and misfolded proteins when extracellular nutrients are deficient [1, 2]. Autophagy is important for maintaining basal cellular homeostasis under normal conditions [3]. Under stress conditions, such as cancer, serum deprivation, and oxidative stress, autophagy is activated to adapt to the stress-induced structural remodeling by synthesizing more nutrients and energy, removing intracellular long-lived or misfolded proteins, and eliminating superfluous or damaged organelles and invasive microbes [4].

The hallmark of autophagy is the formation of the autophagosome that engulfs cytoplasmic components and impaired organelles. The autophagosome begins with the formation of a double-membrane organelle by engulfing damaged cytosolic components, proteins, organelles and cellular debris, and subsequently fuses with the lysosome [5]. According to the degradation pathway in which the cytoplasmic materials reach the lysosomes, autophagy is classified into 3 types: macroautophagy (referred to as autophagy in this review), microautophagy, and chaperone-mediated autophagy (CMA) [6-9]. Macroautophagy, the most known and canonical form, involves 5 sequential steps, including: (1) the independent membranous structure formed by cytoplasmic components turns into a phagophore during membrane isolation; (2) the elongation of the phagophore; (3) formation of a mature autophagosome as a result of the phagophore swallowing or absorbing degradable materials; (4) formation of an autophagolysosome after fusion of the autophagosome with lysosomes; (5) degradation of engulfed materials by lysosomal and hydrolytic enzymes in the autophagolysosome [10, 11]. Generally, microautophagy selectively degrades damaged and depolarized mitochondria via the autophagy pathway [12, 13]. CMA is another type of autophagy in which specific substrates bearing a targeting motif are recognized by a chaperone that delivers them to the lysosomal receptor lysosome-associated membrane protein type 2A to be finally degraded in the lysosomal lumen [8, 14].

Autophagy is regulated by many signaling pathways involving the serine/threonine kinase and mammalian target of rapamycin (mTOR). The mTOR pathway is one of the most studied pathways that regulates autophagy [15]. mTOR inhibition is well known to induce autophagy under stress conditions [16]. Two functional mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), have been found to regulate autophagy. PI3K signaling has been reported to be the major signaling pathway controlling mTORC1 [17]. Recent studies have shown that autophagy is regulated by various signaling pathways and small molecules via mTOR-independent mechanisms [10, 18]. For example, the AMPK pathway [19] and the MEK/ERK pathway [20] have been found to regulate autophagy.

Autophagic flux, the complete dynamic process of autophagy, includes multiple steps involving the formation of phagosomes and autophagosomes, autophagosome fusion with lysosomes, the degradation of the intra-autophagosomal contents, and recycling [21]. Several drugs have been identified to distinguish each step in autophagic flux. For example, Torin1 and the mTOR inhibitor rapamycin can induce autophagy [22, 23]. 3-Methyladenine (3-MA) blocks the formation of autophagosomes by inhibiting class III PI3K [24]. Bafilomycin A1 inhibits lysosome acidification and lysosome degradation by inhibiting V-ATPase. In addition, bafilomycin A1 is also used to inhibit autolysosome degradation and to study LC3-II-mediated autophagic flux [25].

Autophagy in Retinal Pigment Epithelium

Several studies have recently found that a high basal autophagic level is maintained in the retina, particularly in the retinal pigment epithelium (RPE) and photoreceptor cells in mice, and that light exposure causes an autophagic response [26-29]. RPE cells are postmitotic phagocytes that are not self-renewing; therefore, the autophagy of intracellular components is essential for a normal cellular function of the RPE. Maintenance of a high basal level of autophagic activity in the RPE is important for cellular homeostasis and normal function of the visual system.

The autophagic function of RPE cells changes with age and diseases [27]. The levels of autophagy-associated proteins LC3, ATG9, and ATG7 have been reported to increase in the RPE and retinal layers from samples of patients with age-related macular degeneration (ARMD) and in mouse models of ARMD [28]. In addition, Mitter et al. [30] reported that samples from patients with advanced ARMD showed decreased levels of LC3, ATG9, and ATG7, suggesting that impaired autophagic activity causes late-stage ARMD.

Several lines of evidence have demonstrated that impaired autophagy in RPE cells leads to early signs of retinal degeneration, which may contribute to the patho-genesis of retinal diseases such as ARMD and retinitis pigmentosa [31-33]. Zhu et al. [31] found that the upregulation of autophagy protected H2O2-treated RPE cells from necrotic death and that the inhibition of autophagy by LY294002 abolished this protective effect, suggesting that the regulation of autophagy may be a new strategy for treating retinitis pigmentosa. In addition, Flores-Bellver et al. [32] reported that autophagy promoted cell survival in ARPE-19 cells treated with ethanol and that autophagy inhibition by 3-MA increased cell death in ethanol-treated cells, suggesting that autophagy reduces ethanol-induced cell death by degrading fragmented mitochondria and protein inclusions. Furthermore, Liu et al. [33] demonstrated that impairing autophagy induced RPE degeneration and apoptosis, which in turn promoted macrophage inflammasome activation, eventually resulting in an increase in inflammation-induced cytotoxicity and angiogenesis in the eye.

Autophagy in Photoreceptors

Autophagy occurs ubiquitously during various cellular activities of photoreceptors, such as photoreceptor outer segment degeneration [34], rhodopsin protein expression [35], visual cycle formation, and photoreceptor apoptosis [29]. In addition, autophagy has been found to regulate the ultrastructure and function of photoreceptors and to alter their survival and death [36, 37]. Wang et al. [38] found that inducing autophagy significantly suppressed light-induced photoreceptor death and photoreceptor neural degeneration through the turnover of toxic rhodopsin.

Autophagy plays an important role in protecting photoreceptors from death. Rodríguez-Muela et al. [39] found that autophagic flux was blocked in rd10 retinas before the onset of photoreceptor cell death, suggesting that autophagy blockade contributes to photoreceptor cell death. Moreover, Chen et al. [29] discovered that the autophagosome marker LC3B-II was significantly increased in response to light exposure at a dose to cause retinal degeneration in wild-type mice but not in autophagy-deficient mice, suggesting that inadequate autophagy resulted in light-induced retinal degeneration. Furthermore, in the rds/rds mice with a missense mutation in the Pde6b gene (an animal model of retinitis pigmentosa), the autophagy gene expression was delayed, accompanied by the presence of TUNEL-positive photoreceptor cells, suggesting that autophagy is important for clearing photoreceptor cell debris in this retina [40].

The role of autophagy in the regulation of photoreceptor survival has been further studied using autophagy-deficient models. Midorikawa et al. [41] discovered that in the Drosophila visual system, light-dependent retinal degeneration was caused by the knockdown or mutation of autophagy-essential genes, such as Atg7 and Atg8, or genes essential for autophagosome formation. Zhou et al. [42] found that the loss of autophagy caused by a deletion of the essential autophagy gene Atg5 in rods led to progressive degeneration of rod photoreceptors in mice raised without daily light exposure. In mice with a deletion of Atg5 in rods, the function of cone photoreceptors was significantly decreased, although the structure of cone photoreceptors was preserved [42]. These findings suggest that autophagy is important for protecting both cone and rod photoreceptors. Therefore, further understanding of the mechanisms by which autophagy affects photoreceptor survival and death will facilitate the identification of potential therapeutic targets for treating photoreceptor-related retinal diseases.

Autophagy in Retinal Ganglion Cells

Autophagy- related proteins are strongly expressed in the retinal ganglion cell (RGC) layer with high metabolic demand for cell survival, especially during stress, such as retinal ischemia, elevated intraocular pressure and optic nerve transection [43, 44]. Autophagy dysregulation contributes to several ocular diseases, such as cataracts, diabetic retinopathy, and ganglion cell degeneration [45]. Increased autophagy can reduce oxidative stress and promote RGC survival [46]. Cells from autophagy-deficient animals had increased levels of reactive oxygen species (ROS), possibly because impaired autophagy mediated the elimination of oxidized cellular components [47]. Because oxidative stress is increased in experimentally induced glaucoma [48, 49], increased autophagy may represent a new strategy for treating glaucoma by reducing oxidative stress.

Autophagy is neuroprotective and enhances the survival of RGCs. Autophagy is upregulated in RGCs after increasing intraocular pressure (IOP), retinal ischemia, optic nerve transection (ONT), axotomy, or optic nerve crush [50]. After chronic IOP elevation, autophagosomes were significantly accumulated, and LC3-II/LC3-I and beclin-1 were increased in RGCs, suggesting that autophagy is activated in RGCs and that active autophagy may contribute to RGC cell death induced by chronic IOP elevation. Park et al. [51] found that after IOP elevation, most LC3B-positive cells were TUNEL-positive, suggesting that RGC apoptosis occurs with autophagy activation. However, not all of the TUNEL-positive RGCs showed autophagy activation. Some RGCs underwent apoptosis without autophagy activation. After the inhibition of autophagy with 3-MA, the percentage of RGC apoptosis significantly decreased [51]. These results suggest that the activation of autophagy resulted in the apoptosis of some, but not all, RGCs. Furthermore, under starvation conditions, the silencing of Becn1 prevented the induction of autophagy and increased cell death, suggesting that autophagy plays a prosurvival role in RGC cells [50]. The inhibition of autophagy by 3-MA decreased cell viability, suggesting that autophagy activation plays a neuroprotective role [50, 51].

Autophagy is important for preventing spontaneous neurodegeneration. Studies have shown that genetic downregulation of autophagy increases RGC death, whereas pharmacological upregulation of autophagy reduces RGC loss [52]. In a mouse model of ONT, autophagy is upregulated, before RGC cell death, and autophagy upregulation by pharmacological agents reduces axotomy-induced RGC loss. In addition, in Atg4B-knockout mice with a reduced autophagy activity, the number of surviving RGCs was significantly reduced after ONT. Moreover, the specific deletion of the autophagy essential gene Atg5 in retinal neurons before ONT results in a significant decrease in the number of surviving retinal ganglion cells [46]. These findings support that autophagy protects RGCs from traumatic injury. Thus, autophagy modulation may represent a new therapeutic target to ameliorate RGC degeneration in retinal diseases.

Autophagy in Müller Cells

Müller cells span the entire thickness of the retina and are the principal retinal glial cells that mediate the retinal response to damage [53]. Several neurodegenerative diseases, such as glaucoma and retinitis pigmentosa, have been reported to induce the reactive gliosis of Müller cells with a rapid and massive accumulation of glial fibrillary acidic protein (GFAP) [54-56]. GFAP is exclusively expressed in the end feet of Müller cells, and GFAP is a marker for Müller cell activation [57]. Following ischemia/reperfusion, GFAP immunoreactivity was strongly upregulated, particularly in the end feet and in the radial processes of Müller cells, and autophagy inhibitor 3-MA inhibited ischemia/reperfusion-induced upregulation of GFAP. In addition, autophagy inhibition reduced the activation of Müller cells and inhibited astrogliosis in damaged retinas, suggesting that the inhibition of autophagy prevents Müller cell activity during ischemia/reperfusion injury [58]. Lopes de Faria et al. [59] reported that high glucose upregulated autophagy in retinal Müller cells and induced lysosomal impairment, which represent early events in the pathogenesis of diabetic retinopathy.

The Role of Autophagy during Retinal Development and Differentiation

Cell death occurs in different phases of the embryonic development of the retina and affects various retinal cells such as neural stem cells, undifferentiated neuroblasts, newly differentiated neurons, and glial cells. This process ensures correct generation of the retina [60]. Autophagy inhibition can induce cell death, suggesting that autophagy protects retinal cells during development [61].

Autophagy is involved in the differentiation of various cell types, such as erythrocytes, lymphocytes, and adipocytes [62]. Many neurotrophic factors mediate the activation of the PI3K/Akt/mTOR pathway and thus modulate autophagy in the retina in physiological conditions [63]. In the developing Drosophila retina, neurogenesis is controlled by the InR/mTOR pathway. Activation of the InR/mTOR pathway promotes precocious differentiation of photoreceptor neurons, and the inhibition of the InR/mTOR pathway resulted in delayed differentiation [64]. Stem cells isolated from the olfactory bulb of autophagy-deficient mice differentiate into fewer neurons in vitro and alter the process of neuritogenesis and axonogenesis [65], suggesting that autophagy promotes the differentiation of the retina.

The Crosstalk between Autophagy and the Ubiquitin-Proteasome Systemin the Retina

The ubiquitin-proteasome system (UPS) is an intracellular pathway to eliminate misfolded or damaged proteins that originate from cells under both physiological and pathological conditions [66]. The UPS exists throughout the retina, and changes in the UPS and autophagy have been found in the retina of chronically diabetic rats [67]. Proteasome inhibition can activate autophagy [68], in which p62 acts as a bridge [69]. Proteotoxic stress induced by proteasome inhibition can induce p62 phosphorylation, which increases its binding to ubiquitinated proteins [70]. This increased affinity of p62 to ubiquitinated proteins can in turn stabilize ubiquitinated proteins, thereby preventing p62 dephosphorylation and further resulting in protein degradation [71]. However, autophagy inactivation weakens the UPS by increasing p62, which delays the delivery of substrates to the proteasome without changes in proteasomal catalytic activity [72].

The Link between Autophagy and Inflammasome in the Retina

Abnormal inflammation disrupts cellular homeostasis, and autophagy contributes to reduced inflammatory responses [73]. After inflammasome activation by activated microglia, LC3-II is elevated in ARPE-19 cells [74]. Upregulated autophagy induced by rapamycin decreased the oxidative stress-induced generation of ROS, whereas downregulated autophagy increased ROS generation [30]. In the retinas of old Igf1–/– mice, the activation of the inflammasome was associated with the blockade of the autophagic flux. Autophagy inhibition induced retinal gliosis in these mice. In addition, autophagosome accumulation in the inner nuclear and outer plexiform layers concurs with the presence of activated microglia [75, 76], suggesting that autophagy is crucial in protecting the retina against inflammation.

Basal CMA exists in retinal cells and is activated under stress conditions in a manner similar to macroautophagy. CMA activity is upregulated in the aging retina, while in most organs, the activity of CMA declines with age [77, 78]. Within response to the stress, CMA activation occurs later but lasts longer than macroautophagy [79]. Compared with other tissues, CMA-macroautophagy cross-talk in the retina appears not to be bidirectional. Although macroautophagy downregulation leads to a robust increase in CMA, CMA inhibition does not increase macroautophagy, leaving the retina vulnerable to extraneous stressors [78]. In addition, CMA is compensatorily increased during retinal neurodegeneration and protects retinal cells when macroautophagy is compromised [78].

Cell death in response to variety of stressors is a complex process that is controlled by both autophagy and apoptosis, and the cross-talk between autophagy and apoptosis is sometimes complicated (Fig. 1) [80]. The final fate of cells is determined by the results of cross-talk between autophagy and apoptosis. Synergistic and antagonistic roles for autophagy and apoptosis have been reported in the literature. For example, autophagy and apoptosis can function as partners by acting dependently or independently to promote cell death [51, 81]. In addition, the antiapoptotic Bcl-2 and Bcl-XL proteins negatively regulate autophagy by binding to beclin 1, and proapoptotic BH3-only proteins reverse this effect by displacing these interactions [82, 83]. In contrast, apoptosis can suppress autophagy under some conditions of extreme cellular stress. For example, Luo et al. [84] reported that the proapoptotic protein Bax induced apoptosis but reduced autophagy by enhancing the caspase-mediated cleavage of beclin 1. Autophagy antagonizes apoptotic cell death by promoting cell survival through the removal of damaged organelles that are a source of genotoxic ROS, by catabolizing cellular macromolecules to provide a source of nutrients and energy for the starved cell, or by limiting endoplasmic reticulum stress through the degradation of unfolded protein aggregates (Fig. 2) [80, 85]. In addition, autophagy, although not leading to cell death by itself, can induce apoptosis by participating in apoptotic processes, such as ATP-dependent events and phosphatidylserine exposure and membrane blebbing [86, 87].

Fig. 1.

Retinal cell death in response to a variety of stressors is a complex process controlled by both autophagy and apoptosis. The final fate of cells is determined by the results of cross-talk between autophagy and apoptosis. Synergistic and antagonistic roles exist between autophagy and apoptosis. Autophagy and apoptosis can function as partners by acting dependently or independently to promote cell death.

Fig. 1.

Retinal cell death in response to a variety of stressors is a complex process controlled by both autophagy and apoptosis. The final fate of cells is determined by the results of cross-talk between autophagy and apoptosis. Synergistic and antagonistic roles exist between autophagy and apoptosis. Autophagy and apoptosis can function as partners by acting dependently or independently to promote cell death.

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Fig. 2.

Autophagy and apoptosis can induce cell death independently in the same retinal cell. Autophagy can occur before neuronal apoptosis. Autophagy antagonizes apoptosis by promoting cell survival through the removal of damaged organelles, by catabolizing cellular macromolecules to provide nutrients and energy for starved cells, or by limiting endoplasmic reticulum (ER) stress through the degradation of unfolded protein aggregates.

Fig. 2.

Autophagy and apoptosis can induce cell death independently in the same retinal cell. Autophagy can occur before neuronal apoptosis. Autophagy antagonizes apoptosis by promoting cell survival through the removal of damaged organelles, by catabolizing cellular macromolecules to provide nutrients and energy for starved cells, or by limiting endoplasmic reticulum (ER) stress through the degradation of unfolded protein aggregates.

Close modal

In retinal cells, low glucose-induced apoptosis is involved in autophagosome formation through the AMPK/RAPTOR/mTOR pathway [88]. The specific inhibition of autophagy, either by 3-MA or the downregulation of ATG5 or ATG7 protein expression, increased caspase 3 activation and induced 661W cell death. These results suggest that cells struggle against low nutrient-induced apoptosis by initiating an autophagic process but failed to survive when autophagy is inhibited [88]. In murine cytomegalovirus-induced retinal apoptosis, autophagy induced by rapamycin inhibited apoptosis [89]. Using a well-established Drosophila model with the constitutively active TRPP365 channels, Huang et al. [90] found that upregulated autophagy flux prevented TRPP365-induced photoreceptor cell death in mutant flies. Rodriguez-Muela et al. [46] demonstrated that autophagy can promote the survival of RGCs following ONT in mice. These studies support the antagonistic role for autophagy and apoptosis in retinal cells. However, the autophagosome accumulation induced by ethambutol led to impaired autophagic flux in a PKCδ-dependent manner and inhibited the PI3K/Akt/mTOR signaling pathway, eventually resulting in apoptotic death in retina neuronal cells [91]. Park et al. [46, 51] reported that the activation of autophagy results in the apoptosis of RGCs in a chronic glaucoma model.

Although autophagy and apoptosis can coexist in the same damaged RGC, they do not necessarily overlap and can occur independently [58, 92]. Autophagy can occur before neuronal apoptosis in aluminum-insulted astrocytes, a chronic hypertensive glaucoma model, and an optic nerve axotomy mouse model [46, 93, 94]. Similarly, in a chronic glaucoma model, autophagy activation occurs earlier than RGC loss [58]. Taken together, normal or high levels of autophagy defend cells against external stress; however, excessive autophagy can lead to deterioration in the retina.

The exact relationship between autophagy and the retina remains unknown and warrants further exploration. Several questions remain: how does autophagy progress in retinal disease? What are the relationships between the regulatory pathways of autophagy? What is the relationship between autophagy and functional recovery of the retina? What are the complicated molecular mechanisms for regulating the interaction of apoptosis and autophagy? A more thorough understanding of autophagy and apoptosis in the retina will aid in preventing and treating retinal disease. Because autophagy plays a dual role (as a cytoprotector or a cytokiller) in the progression of retinal disease, modulating autophagy may provide an alternative therapeutic strategy for retinal disease. Targeting autophagy may prevent retinal cells from death by inhibiting apoptosis, promoting recycling damaged proteins or organelles for retinal reconstruction, increase clearing of damaged mitochondria to alleviate ROS-induced oxidative stress, and inhibit the activation of retinal microglial cells.

This work was supported by grants from the National Natural Science Foundation of China (No. 81770948).

The authors declare no competing or financial interests.

Fleming A, Noda T, Yoshimori T, Rubinsztein DC: Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 2011; 7: 9–17.
Menzies FM, Fleming A, Rubinsztein DC: Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 2015; 16: 345–357.
Musiwaro P, Smith M, Manifava M, Walker SA, Ktistakis NT: Characteristics and requirements of basal autophagy in HEK 293 cells. Autophagy 2013; 9: 1407–1417.
Kroemer G, Marino G, Levine B: Autophagy and the integrated stress response. Mol Cell 2010; 40: 280–293.
Yang Z, Klionsky DJ: Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12: 814–822.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069–1075.
Boya P, Reggiori F, Codogno P: Emerging regulation and functions of autophagy. Nat Cell Biol 2013; 15: 713–720.
Kaushik S, Cuervo AM: Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 2012; 22: 407–417.
Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L: Microautophagy of cytosolic proteins by late endosomes. Dev Cell 2011; 20: 131–139.
Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, et al: Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90: 1383–1435.
Feng Y, He D, Yao Z, Klionsky DJ: The machinery of macroautophagy. Cell Res 2014; 24: 24–41.
Ashrafi G, Schwarz TL: The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 2013; 20: 31–42.
Khaminets A, Behl C, Dikic I: Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol 2016; 26: 6–16.
Cuervo AM: Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol Metab 2010; 21: 142–150.
Park D, Jeong H, Lee MN, Koh A, Kwon O, Yang YR, Noh J, Suh PG, Park H, Ryu SH: Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci Rep 2016; 6: 21772.
Hasanain M, Bhattacharjee A, Pandey P, Ashraf R, Singh N, Sharma S, Vishwakarma AL, Datta D, Mitra K, Sarkar J: Alpha-solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway. Cell Death Dis 2015; 6:e1860.
Kim J, Kim YC, Fang C, Russell RC, Kim JH, Fan W, Liu R, Zhong Q, Guan KL: Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 2013; 152: 290–303.
Sarkar S: Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 2013; 41: 1103–1130.
Russell RC, Yuan HX, Guan KL: Autophagy regulation by nutrient signaling. Cell Res 2014; 24: 42–57.
Liu P, Zhang Z, Wang Q, Guo R, Mei W: Lithium chloride facilitates autophagy following spinal cord injury via ERK-dependent pathway. Neurotox Res 2017; 32: 535–543.
Klionsky DJ, Abdalla FC, Abeliovich H, Ab-raham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al: Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012; 8: 445–544.
Chung KW, Kim KM, Choi YJ, An HJ, Lee B, Kim DH, Lee EK, Im E, Lee J, Im DS, et al: The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis. Autophagy 2017: 1–17.
Bae SY, Byun S, Bae SH, Min DS, Woo HA, Lee K: TPT1 (tumor protein, translationally-controlled 1) negatively regulates autophagy through the BECN1 interactome and an MTORC1-mediated pathway. Autophagy 2017; 13: 820–833.
Chang CH, Lee CY, Lu CC, Tsai FJ, Hsu YM, Tsao JW, Juan YN, Chiu HY, Yang JS, Wang CC: Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: a key role of AMPK and Akt/mTOR signaling. Int J Oncol 2017; 50: 873–882.
Tanida I, Waguri S: Measurement of autophagy in cells and tissues. Methods Mol Biol 2010; 648: 193–214.
Kaarniranta K, Sinha D, Blasiak J, Kauppinen A, Vereb Z, Salminen A, Boulton ME, Petrovski G: Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration. Autophagy 2013; 9: 973–984.
Mitter SK, Rao HV, Qi X, Cai J, Sugrue A, Dunn WA Jr, Grant MB, Boulton ME: Autophagy in the retina: a potential role in age-related macular degeneration. Adv Exp Med Biol 2012; 723: 83–90.
Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH: Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration. PLoS One 2009; 4: e4160.
Chen Y, Sawada O, Kohno H, Le YZ, Subauste C, Maeda T, Maeda A: Autophagy protects the retina from light-induced degeneration. J Biol Chem 2013; 288: 7506–7518.
Mitter SK, Song C, Qi X, Mao H, Rao H, Akin D, Lewin A, Grant M, Dunn W Jr, Ding J, et al: Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 2014; 10: 1989–2005.
Zhu Y, Zhao KK, Tong Y, Zhou YL, Wang YX, Zhao PQ, Wang ZY: Exogenous NAD(+) decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy. Sci Rep 2016; 6: 26322.
Flores-Bellver M, Bonet-Ponce L, Barcia JM, Garcia-Verdugo JM, Martinez-Gil N, Saez-Atienzar S, Sancho-Pelluz J, Jordan J, Galindo MF, Romero FJ: Autophagy and mitochondrial alterations in human retinal pigment epithelial cells induced by ethanol: implications of 4-hydroxy-nonenal. Cell Death Dis 2014; 5:e1328.
Liu J, Copland DA, Theodoropoulou S, Chiu HA, Barba MD, Mak KW, Mack M, Nicholson LB, Dick AD: Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis. Sci Rep 2016; 6: 20639.
Kim JY, Zhao H, Martinez J, Doggett TA, Kolesnikov AV, Tang PH, Ablonczy Z, Chan CC, Zhou Z, Green DR, Ferguson TA: Noncanonical autophagy promotes the visual cycle. Cell 2013; 154: 365–376.
Mohlin C, Taylor L, Ghosh F, Johansson K: Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina. Brain Res 2014; 1585: 167–183.
Bogea TH, Wen RH, Moritz OL: Light induces ultrastructural changes in rod outer and inner segments, including autophagy, in a transgenic Xenopus laevis P23H rhodopsin model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 2015, 56: 7947–7955.
Zhou Z, Vinberg F, Schottler F, Doggett TA, Kefalov VJ, Ferguson TA: Autophagy supports color vision. Autophagy 2015, 11: 1821–1832.
Wang T, Lao U, Edgar BA: TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 2009; 186: 703–711.
Rodriguez-Muela N, Hernandez-Pinto AM, Serrano-Puebla A, Garcia-Ledo L, Latorre SH, de la Rosa EJ, Boya P: Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa. Cell Death Differ 2015; 22: 476–487.
Kunchithapautham K, Rohrer B: Autophagy is one of the multiple mechanisms active in photoreceptor degeneration. Autophagy 2007; 3: 65–66.
Midorikawa R, Yamamoto-Hino M, Awano W, Hinohara Y, Suzuki E, Ueda R, Goto S: Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila. J Neurosci 2010; 30: 10703–10719.
Zhou Z, Doggett TA, Sene A, Apte RS, Ferguson TA: Autophagy supports survival and phototransduction protein levels in rod photoreceptors. Cell Death Differ 2015; 22: 488–498.
Wei T, Kang Q, Ma B, Gao S, Li X, Liu Y: Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats. Exp Ther Med 2015; 9: 476–482.
Munemasa Y, Kitaoka Y: Autophagy in axonal degeneration in glaucomatous optic neuropathy. Prog Retin Eye Res 2015; 47: 1–18.
Li YJ, Jiang Q, Cao GF, Yao J, Yan B: Repertoires of autophagy in the pathogenesis of ocular diseases. Cell Physiol Biochem 2015; 35: 1663–1676.
Rodriguez-Muela N, Germain F, Marino G, Fitze PS, Boya P: Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. Cell Death Differ 2012; 19: 162–169.
Boya P: Why autophagy is good for retinal ganglion cells? Eye (Lond) 2017; 31: 185–190.
Pinazo D, Shoaie-Nia K, Zanon-Moreno V, Sanz-Gonzalez SM, Del Castillo JB, Garcia-Medina JJ: Strategies to reduce oxidative stress in glaucoma patients. Curr Neuropharmacol 2017, Epub ahead of print.
Panchal SS, Patidar RK, Jha AB, Allam AA: Anti-inflammatory and antioxidative stress effects of oryzanol in glaucomatous rabbits. J Ophthalmol 2017; 2017: 1468716.
Lin WJ, Kuang HY: Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells. Autophagy 2014; 10: 1692–1701.
Park HY, Kim JH, Park CK: Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model. Cell Death Dis 2012; 3:e290.
Russo R, Nucci C, Corasaniti MT, Bagetta G, Morrone LA: Autophagy dysregulation and the fate of retinal ganglion cells in glaucomatous optic neuropathy. Prog Brain Res 2015; 220: 87–105.
Pannicke T, Ivo Chao T, Reisenhofer M, Francke M, Reichenbach A: Comparative electrophysiology of retinal Muller glial cells – a survey on vertebrate species. Glia 2017; 65: 533–568.
Ji M, Miao Y, Dong LD, Chen J, Mo XF, Jiang SX, Sun XH, Yang XL, Wang Z: Group I mGluR-mediated inhibition of Kir channels contributes to retinal Muller cell gliosis in a rat chronic ocular hypertension model. J Neurosci 2012; 32: 12744–12755.
Gao F, Li F, Miao Y, Xu LJ, Zhao Y, Li Q, Zhang SH, Wu J, Sun XH, Wang Z: Involvement of the MEK-ERK/p38-CREB/c-fos signaling pathway in Kir channel inhibition-induced rat retinal Muller cell gliosis. Sci Rep 2017; 7: 1480.
He X, Sun D, Chen S, Xu H: Activation of liver X receptor delayed the retinal degeneration of rd1 mice through modulation of the immunological function of glia. Oncotarget 2017; 8: 32068–32082.
Koenekoop RK: Why do cone photoreceptors die in rod-specific forms of retinal degenerations? Ophthalmic Genet 2009; 30: 152–154.
Piras A, Gianetto D, Conte D, Bosone A, Vercelli A: Activation of autophagy in a rat model of retinal ischemia following high intraocular pressure. PLoS One 2011; 6:e22514.
Lopes de Faria JM, Duarte DA, Montemurro C, Papadimitriou A, Consonni SR, Lopes de Faria JB: Defective autophagy in diabetic retinopathy. Invest Ophthalmol Vis Sci 2016; 57: 4356–4366.
Boya P, de la Rosa EJ: Cell death in early neural life. Birth Defects Res C Embryo Today 2005; 75: 281–293.
Guimaraes CA, Benchimol M, Amarante-Mendes GP, Linden R: Alternative programs of cell death in developing retinal tissue. J Biol Chem 2003; 278: 41938–41946.
Mizushima N, Levine B: Autophagy in mammalian development and differentiation. Nat Cell Biol 2010; 12: 823–830.
Boya P, Esteban-Martinez L, Serrano-Puebla A, Gomez-Sintes R, Villarejo-Zori B: Autophagy in the eye: development, degeneration, and aging. Prog Retin Eye Res 2016; 55: 206–245.
McNeill H, Craig GM, Bateman JM: Regulation of neurogenesis and epidermal growth factor receptor signaling by the insulin receptor/target of rapamycin pathway in Drosophila. Genetics 2008; 179: 843–853.
Vazquez P, Arroba AI, Cecconi F, de la Rosa EJ, Boya P, de Pablo F: Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy 2012; 8: 187–199.
Campello L, Esteve-Rudd J, Cuenca N, Martin-Nieto J: The ubiquitin-proteasome system in retinal health and disease. Mol Neurobiol 2013; 47: 790–810.
Shruthi K, Reddy SS, Reddy GB: Ubiquitin-proteasome system and ER stress in the retina of diabetic rats. Arch Biochem Biophys 2017; 627: 10–20.
Tang B, Cai J, Sun L, Li Y, Qu J, Snider BJ, Wu S: Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells. PLoS One 2014; 9:e103364.
Cortes CJ, La Spada AR: Autophagy in polyglutamine disease: imposing order on disorder or contributing to the chaos? Mol Cell Neurosci 2015; 66: 53–61.
Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, Komatsu M, Oh YJ, Zhao Y, Yue Z: Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet 2015; 11:e1004987.
Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N: Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 2011; 44: 279–289.
Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC: Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 2009; 33: 517–527.
Lapaquette P, Guzzo J, Bretillon L, Bringer MA: Cellular and molecular connections between autophagy and inflammation. Mediators Inflamm 2015; 2015: 398483.
Nebel C, Aslanidis A, Rashid K, Langmann T: Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells. Biochem Biophys Res Commun 2017; 484: 681–686.
Arroba AI, Rodriguez-de la Rosa L, Murillo-Cuesta S, Vaquero-Villanueva L, Hurle JM, Varela-Nieto I, Valverde AM: Autophagy resolves early retinal inflammation in Igf1-deficient mice. Dis Model Mech 2016; 9: 965–974.
Shen DN, Zhang LH, Wei EQ, Yang Y: Autophagy in synaptic development, function, and pathology. Neurosci Bull 2015, 31: 416–426.
Zhang C, Cuervo AM: Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008; 14: 959–965.
Rodriguez-Muela N, Koga H, Garcia-Ledo L, de la Villa P, de la Rosa EJ, Cuervo AM, Boya P: Balance between autophagic pathways preserves retinal homeostasis. Aging Cell 2013; 12: 478–488.
Tasset I, Cuervo AM: Role of chaperone-mediated autophagy in metabolism. Febs J 2016; 283: 2403–2413.
Marino G, Niso-Santano M, Baehrecke EH, Kroemer G: Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15: 81–94.
Zhang D, Qiu W, Wang P, Zhang P, Zhang F, Wang P, Sun Y: Autophagy can alleviate severe burn-induced damage to the intestinal tract in mice. Surgery 2017; 162: 408–417.
Robert G, Gastaldi C, Puissant A, Hamouda A, Jacquel A, Dufies M, Belhacene N, Colosetti P, Reed JC, Auberger P, Luciano F: The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death. Autophagy 2012; 8: 637–649.
He C, Levine B: The beclin 1 interactome. Curr Opin Cell Biol 2010; 22: 140–149.
Luo S, Rubinsztein DC: Apoptosis blocks beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 2010; 17: 268–277.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, et al: Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137: 1062–1075.
Fang KM, Liu JJ, Li CC, Cheng CC, Hsieh YT, Chai KM, Lien YA, Tzeng SF: Colchicine derivative as a potential anti-glioma compound. J Neurooncol 2015; 124: 403–412.
Ramundo S, Rochaix JD: Chloroplast unfolded protein response, a new plastid stress signaling pathway? Plant Signal Behav 2014; 9:e972874.
Balmer D, Emery M, Andreux P, Auwerx J, Ginet V, Puyal J, Schorderet DF, Roduit R: Autophagy defect is associated with low glucose-induced apoptosis in 661W photoreceptor cells. PLoS One 2013; 8:e74162.
Mo J, Zhang M, Marshall B, Smith S, Covar J, Atherton S: Interplay of autophagy and apoptosis during murine cytomegalovirus infection of RPE cells. Mol Vis 2014; 20: 1161–1173.
Huang Z, Ren S, Jiang Y, Wang T: PINK1 and parkin cooperatively protect neurons against constitutively active TRP channel-induced retinal degeneration in Drosophila. Cell Death Dis 2016; 7:e2179.
Huang SP, Chien JY, Tsai RK: Ethambutol induces impaired autophagic flux and apoptosis in the rat retina. Dis Model Mech 2015; 8: 977–987.
Deng S, Wang M, Yan Z, Tian Z, Chen H, Yang X, Zhuo Y: Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model. PLoS One 2013; 8:e77100.
Zeng KW, Fu H, Liu GX, Wang XM: Aluminum maltolate induces primary rat astrocyte apoptosis via overactivation of the class III PI3K/beclin 1-dependent autophagy signal. Toxicol In Vitro 2012; 26: 215–220.
Su W, Li Z, Jia Y, Zhuo Y: Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model. PLoS One 2014; 9:e99719.
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