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.

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