Newly-found functions of metformin for the prevention and treatment of age-related macular degeneration

AIM: To explore the temporal mitochondrial characteristics of retinal pigment epithelium (RPE) cells obtained from human embryonic stem cells (hESC)-derived retinal organoids (hEROs-RPE), to verify the optimal period for using hEROs-RPE as donor cells from the aspect of mitochondria and to optimize RPE cell-based therapeutic strategies for age-related macular degeneration (AMD). METHODS: RPE cells were obtained from hEROs and from spontaneous differentiation (SD-RPE). The mitochondrial characteristics were analyzed every 20d from day 60 to 160. Mitochondrial quantity was measured by MitoTracker Green staining. Transmission electron microscopy was adopted to assess the morphological features of the mitochondria, including their distribution, length, and cristae. Mitochondrial membrane potentials (MMPs) were determined by JC-1 staining and flow cytometry. ROS levels were evaluated by flow cytometry, and ATP levels were measured by a luminometer. Differences between two groups were analyzed by the independent-samples t-test, and comparisons among multiple groups were made using one-way ANOVA or Kruskal-Wallis H test when equal variance is not assumed. RESULTS: hEROs-RPE and SD-RPE cells from day 60 to 160 were successfully differentiated from hESCs and expressed RPE-specific markers (Pax6, mitf, Bestrophin-1, RPE65, Cralbp). RPE features, including a cobblestone-like morphology with tight junctions (ZO-1), pigments and microvilli, were also observed in both hERO-RPE and SD-RPE cells. The mitochondrial quantities peaked in both hEROs-RPE and SD-RPE cells at day 80. However, the cristae of hEROs mitochondria were less mature and abundant than those of SD mitochondria at day 80, with hEROs mitochondria becoming mature at day 100. Both hEROs-RPE and SD-RPE cells showed low ROS levels from day 100 to 140 and maintained a normal MMP during this period. However, hEROs mitochondria maintained a longer time to produce high levels of ATP (from day 120 to 140) than SD-RPE cells (only day 120). CONCLUSION: Mitochondria of hEROs-RPE cells develop slower and maintain a longer time to supply high-levels of energy than SD-RPE cells. From a mitochondrial aspect, hEROs-RPE cells from day 100 to 140 are an optimal cell source for treating AMD.     

压力升高诱导的视网膜神经节细胞-5的凋亡和自噬

背景 研究表明线粒体途径的凋亡和自噬均是影响青光眼视网膜神经节细胞(RGCs)存活的重要因素,但压力是否引发RGCs线粒体途径的凋亡和自噬尚未阐明. 目的 探讨压力对体外培养的RGCs线粒体途径凋亡和自噬的影响. 方法 将培养的RGC-5细胞分为正常对照组及0、20、40和60 mmHg(1 mmHg=0.133 kPa)压力组,根据分组使用自制加压装置对离体培养的RGC-5细胞密闭加压处理4h,倒置相差显微镜下观察各组细胞的形态学变化,采用流式细胞仪检测细胞的凋亡和坏死率,采用JC-1荧光染料检测细胞线粒体膜电位的改变,采用Western blot法检测各组细胞中细胞色素C(Cyt-c)、微管相关蛋白轻链3(LC3)和Beclin-1的表达.结果 正常对照组和0 mmHg压力组培养的RGC-5细胞呈梭形,可见较多的树突,而20、40和60 mmHg压力组随着压力的增大,细胞密度变小,部分细胞树突缩短且变少,死亡细胞增多.正常对照组及0、20、40和60 mmHg压力组总凋亡和坏死细胞比例分别为(15.69±0.77)％、(15.77±1.14)％、(18.30±1.07)％、(23.28±1.33)％和(34.47±1.17)％,总体比较差异有统计学意义(F=150.90,P＜0.001),其中40 mmHg压力组和60 mmHg压力组总凋亡和坏死细胞率明显高于正常对照组,差异均有统计学意义(均P＜0.01).正常对照组细胞线粒体膜电位呈橙色荧光,20 mmHg压力组和40 mmHg压力组细胞荧光强度减弱,橙色变淡,60 mmHg压力组细胞呈绿色荧光.与正常对照组比较,60 mmHg压力组细胞中Cyt-c蛋白相对表达量明显增加,40 mmHg压力组和60 mmHg压力组细胞中LC3-Ⅱ的相对表达量明显增加,20、40和60 mmHg压力组细胞中Beclin-1的相对表达量明显增加,差异均有统计学意义(均P＜0.05).结论 压力升高可诱导体外培养的RGC-5细胞形态异常,导致细胞线粒体膜电位下降,并通过线粒体途径发生凋亡和自噬.     

线粒体融合和裂变在眼科疾病中的研究进展

线粒体是多细胞生命不可缺少的组成部分,通过裂变和融合进行形态上的变化和空间上的重新排列以适应细胞的需求,维持能量平衡。线粒体的这种控制其自身数量、大小、形状和在细胞内的分布特征被称为线粒体动力学。正常情况下,线粒体融合-裂变是平衡的,当细胞早期受到应激时,受损的线粒体首先通过裂变和融合来维持其功能的正常运行。线粒体功能异常可能与细胞的衰老和凋亡密切相关,因此,本文就线粒体动力学包括线粒体裂变和融合在常见眼科疾病中的研究进展进行综述。     

Responses of different cell lines from ocular tissues to elevated hydrostatic pressure

BACKGROUND/AIMS: Mechanical forces are thought to induce cellular responses through activation of signalling pathways. Cells within the intraocular environment are exposed to constant changes in the levels of intraocular pressure. In this study, an attempt was made to determine the acute effects of elevated hydrostatic pressure on different intraocular cells grown in culture. METHODS: Different cell lines derived from ocular tissues including non-pigmented and pigmented ciliary epithelium, trabecular meshwork, retina, and lamina cribrosa were incubated in a pressurised chamber at 50 mm Hg in a culture incubator at 37 degrees C for up to 6 hours. Control cells were incubated at atmospheric pressure. The viability of the cells was examined using their intracellular esterase activity. The morphology and cytoskeleton of the cells were investigated using microscopy and phalloidin staining. Adenylyl cyclase activity was assessed by measuring the conversion of [(3)H]-cAMP from [(3)H]-ATP in response to elevated hydrostatic pressure for 1-6 hours. In addition, at the end of incubation period under elevated hydrostatic pressure the recovery of adenylyl cyclase activity to control levels was examined. RESULTS: Cell viability did not change following exposure to elevated hydrostatic pressure for 6 hours. Cells subjected to elevated hydrostatic pressure demonstrated morphological differences characterised by a more rounded shape and a redistribution of actin stress fibres that was most prominent in lamina cribrosa astrocytes. A time dependent increase in basal adenylyl cyclase activity, and a decrease in maximum forskolin stimulated activity were observed in all cell lines following exposure to elevated hydrostatic pressure. CONCLUSION: These observations demonstrate that cell lines from different ocular tissues are sensitive to changes in external pressure in vitro. They exhibit morphological and cytoskeletal changes as well as significant alterations of intracellular adenylyl cyclase activity following exposure to acute and sustained levels of elevated hydrostatic pressure of up to 6 hours' duration.     

Inhibition of plasminogen activators attenuates the death of differentiated retinal ganglion cells and stabilizes their neurite network in vitro

PURPOSE: Although previous studies have indicated that elevated levels of the tissue plasminogen activator (tPA) and the urokinase plasminogen activator (uPA) associate with the death of retinal ganglion cells (RGCs), it was unclear whether these proteases directly cause cell death. With the use of a transformed and undifferentiated retinal ganglion cell line, RGC-5, which does not express tPA, and by treating this cell line with staurosporine, which induces not only the differentiation of RGC-5 cells but also the expression of uPA and tPA in other neuronal cells, the authors sought to determine whether these proteases regulate the differentiation of RGC-5 cells and whether elevated levels of these proteases directly cause the death of RGC-5 cells. METHODS: Transformed RGC-5 cells were cultured in serum-free medium and were treated with 0.5 muM to 2.0 muM staurosporine to induce their differentiation. Neurite outgrowth was assessed by phase-contrast microscopy and calcein AM staining and quantified with imaging software. Proteolytic activities of tPA and uPA were determined by zymography assays. Cell viability was determined by LIVE/DEAD viability assay kit. RESULTS: Compared with untreated RGC-5 cells, cells treated with staurosporine differentiated as early as 1 to 6 hours. However, proteolytic activities of neither tPA nor uPA were observed within this time frame. Differentiated RGC-5 cells expressed detectable levels of uPA proteolytic activity starting at 24 hours and tPA proteolytic activity only at 48 hours. RGC-5 cells synthesized and secreted uPA and tPA into the conditioned medium, depending on staurosporine concentration and treatment time. At lower concentrations of staurosporine, differentiated RGC-5 cells had longer neurites and expressed lower levels of tPA and uPA. At higher concentrations of staurosporine, differentiated RGC-5 cells expressed higher levels of tPA and uPA, had smaller neurites, and most of them died. In contrast, when RGC-5 cells were treated with staurosporine along with inhibitors specific to tPA and uPA, proteolytic activities of both PAs were significantly reduced. Under these conditions, a significant number of RGC-5 cells survived, showed increased neurite outgrowth, and established their neurite network in vitro. CONCLUSIONS: Results presented in this study indicate that RGC-5 cells do not require tPA and tPA for their differentiation. In fact, differentiated RGC-5 cells synthesize elevated levels of tPA and uPA, and elevated levels of these proteases acting in an autocrine-fashion in turn lead to the death of RGC-5 cells.     

线粒体动力学与视网膜神经节细胞

线粒体动力学是指细胞中的线粒体不断地分裂、融合、移动、运输和线粒体自噬等,这些动态的过程在调节线粒体的形态与功能中发挥关键作用,并对细胞的存活、代谢、功能等有重要影响.视网膜神经节细胞(RGCs)作为视网膜中一类特殊且重要的神经元,对线粒体的动力学改变特别敏感.有关常染色体显性遗传性视神经萎缩疾病的研究发现,控制线粒体融合的相关基因与RGCs功能密切相关.实验性青光眼模型提示,眼压升高引起RGCs的线粒体分裂增多,改变调节线粒体融合基因的表达,最终诱导RGCs的凋亡;线粒体在RGCs中的正常运输和分布对于RGCs轴突的功能至关重要.以上遗传性和实验性视神经病变的研究表明,线粒体动力学在调节RGCs的生存中发挥着核心作用,通过调控线粒体动力学来保护RGCs可能是一个非常有前景的治疗策略.本文将对线粒体动力学的主要内容和RGCs中的线粒体动力学进行阐述.     

Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage

PURPOSE: To determine whether oxidative adduct formation or heme oxygenase-1 (HO-1) expression are altered in retinal ganglion cell (RGC) cultures exposed to elevated hydrostatic pressure and in a mouse model of glaucoma. METHODS: Cultured RGC-5 cells were subjected to 0, 30, 60, or 100 mm Hg hydrostatic pressure for 2 hours, and the cells were harvested. Parallel experiments examined the recovery from this stress, the effect of direct 4-hydroxy-2-nonenal (HNE) treatment, and the effect of pretreatment with resveratrol or quercetin. Mice were anesthetized and intraocular pressure was increased to 30, 60, or 100 mm Hg for 1 hour; then the retinas were harvested. HNE adduct formation and HO-1 expression were assessed by immunocytochemistry and immunoblotting. RESULTS: Increases of HNE-protein adducts (up to 5-fold) and HO-1 expression (up to 2.5 fold) in pressure-treated RGC-5 cells were dose dependent. During recovery experiments, HNE-protein adducts continued to increase for up to 10 hours; in contrast, HO-1 expression decreased immediately. HNE, at a concentration as low as 5 muM, led to neurotoxicity in RGC-5 cells. HNE adducts and HO-1 expression increased in the mouse retina and optic nerve after acute IOP elevation up to 5.5-fold and 2-fold, respectively. Antioxidant treatment reduced the oxidative stress level in pressure-treated RGC-5 cells. CONCLUSIONS: This study demonstrates that oxidative stress is an early event in hydrostatic pressure/IOP-induced neuronal damage. These findings support the view that oxidative damage contributes early to glaucomatous optic neuropathy.     

硫化氢对H2O2诱导的视网膜神经节细胞氧化损伤的保护作用

目的 探讨硫化氢对H2O2诱导的视网膜神经节细胞(retinal ganglion cell,RGC)-5氧化损伤的保护作用及可能机制.方法 将RGC-5分为4组,RGC-5组为正常对照组;RGC-5+ H2O2组:RGC-5在500 μmol·L-H2 O2中培养24 h诱导氧化损伤;RGC-5+ NaHS+ H2O2组:RGC-5置于50μmol·L-1NaHS中30 min后在500 μmol·L-1H2O2中培养24 h;RGC-5+ NaHS组:RGC-5置于50 μmol·L-1 NaHS中30 min.Western blot检测线粒体内、外细胞色素C和视神经萎缩蛋白1(optic atrophy 1,OPA1)表达;用荧光探针JC-1检测线粒体膜电位,用透射电镜观察线粒体形态.结果 与RGC-5组相比,RGC-5+ H2O2组RGC-5细胞质内细胞色素C表达增加,而线粒体内的OPA1表达减少(均为P＜0.05).RGC-5组和RGC-5+ NaHS+ H2O2组线粒体内、外细胞色素C的表达差异均无统计学意义(均为P＞0.05).与RGC-5组相比,RGC-5+ NaHS组细胞质内细胞色素C表达减少,而线粒体内的细胞色素C表达增加(均为P＜0.05).与RGC-5组相比,RGC-5+H2O2组RGC-5细胞质内OPA1表达显著增加,而线粒体内的OPA1表达减少(均为P＜0.05).RGC-5+ NaHS+H2O2组和RGC-5+NaHS组RGC6线粒体内、外OPA1的表达与RGC-5组相似,差异均无统计学意义(均为P＞0.05).RGC6 +H2O2组线粒体膜电位与其他3组比较明显下降,其余3组间线粒体膜电位比较,差异无统计学意义(P＞0.05).RGC-5+H2O2组线粒体肿胀呈球状,而其余3组线粒体肿胀不明显.结论 硫化氢可能通过阻止线粒体释放OPA1来减轻H2O2导致的RGC-5氧化损伤.     

The effect of elevated hydrostatic pressure on expression level of type III collagen mRNA by lamina cribrosa cells in vitro

OBJECTIVE: To investigate the effect of elevated hydrostatic pressure on the expression level of type III collagen mRNA by lamina cribrosa cells (LCCs) and approach the action of changes of extracellular stroma on glaucomatous optic nerve damage. METHODS: LCCs were cultured and submitted to elevated hydrostatic pressure (4.67 - 5.33 kPa). We observed collagen type III mRNA level by dot-blot hybridization and computer imaging analysis. RESULTS: Under the pressure for 3 days, the amounts of collagen III mRNA were 0.5828 +/- 0.0517 in optical density (OD), compared with the same period controls (0.2832 +/- 0.0613), the difference was statistically significant (P < 0.05). When exposed to pressure up to 6 days, the collagen III mRNA level remained somewhat higher than that of the control, but there was no significant difference (P > 0.05). After 9 to 12 days of exposure to pressure, the mRNA amounts were decreased respectively to 0.3246 +/- 0.0957 and 0.2164 +/- 0.0171 in OD that were lower than that of the control in the respective same periods, and the differences between the experimental and the control had no significance (P > 0.05). CONCLUSION: Elevated hydrostatic pressure may increase expression level of collagen III mRNA by LCCs in a certain period.     

线粒体自噬参与糖尿病视网膜病变的研究进展

线粒体功能对于需氧真核细胞的生存至关重要,因为线粒体通过产生三磷酸腺苷(ATP)提供能量、调节细胞代谢、提供氧化还原平衡、参与免疫信号传导并启动细胞凋亡。线粒体自噬是一种细胞内针对功能障碍线粒体的选择性降解机制,参与线粒体的质量控制及细胞稳态的维持。近年来,越来越多的研究发现异常的线粒体自噬参与多种眼部疾病的发生发展,如糖尿病视网膜病变(DR)、年龄相关性黄斑变性和青光眼等。因此,本文总结已知的线粒体自噬定义,整理各种使用细胞培养、动物和人体组织模型进行研究的结果,并就线粒体自噬的分子生物学过程及其在DR中的作用展开综述,以期为DR的治疗手段提供新思路。     

Mechanisms regulating plasminogen activators in transformed retinal ganglion cells

Irreversible loss of retinal ganglion cells (RGCs) is a major clinical issue in glaucoma, but the mechanisms that lead to RGC death are currently unclear. We have previously reported that elevated levels of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) cause the death of RGCs in vivo and transformed retinal ganglion cells (RGC-5) in vitro. Yet, it is unclear how secreted proteases such as tPA and uPA directly cause RGCs' death. In this study, by employing RGC-5 cells, we report that tPA and uPA elicit their direct effect through the low-density lipoprotein-related receptor-1 (LRP-1). We also show that blockade of protease-LRP-1 interaction leads to a complete reduction in autocrine synthesis of tPA and uPA, and prevents protease-mediated death of RGC-5 cells. RGC-5 cells were cultured in serum-free medium and treated with 2.0 microM Staurosporine to induce their differentiation. Neurite outgrowth was observed by a phase contrast microscope and quantified by NeuroJ imaging software. Proteolytic activities of tPA and uPA were determined by zymography assays. Cell viability was determined by MTT assays. Compared to untreated RGC-5 cells, cells treated with Staurosporine differentiated, synthesized and secreted elevated levels of tPA and uPA, and underwent cell death. In contrast, when RGC-5 cells were treated with Staurosporine along with the receptor associated protein (RAP), proteolytic activities of both tPA and uPA were significantly reduced. Under these conditions, a significant number of RGC-5 cells survived and showed increased neurite outgrowth. These results indicate that LRP-1 regulates autocrine synthesis of tPA and uPA in RGC-5 cells and suggest that the use of RAP to antagonize the effect of proteases may be a way to prevent RGC death in glaucoma.     

压力对培养的人眼筛板细胞及胶原蛋白合成的影响

目的 研究压力对人眼筛板细胞形态这改变及胶原蛋白合成的影响,方法 对筛板细胞进行体外培养,在光镜和电镜下观察压力对人眼筛板细胞形态和结构的影响,并使用显微荧光光度计对筛板细胞胶原蛋白合成进行定量测定。结果 静压力６．６７ｋＰａ（１ｋＰａ＝７．５ｍｍＨｇ）下,筛板细胞向两端延长,形态变扁,随时间的延长,胞浆内空泡增多,线粒体肿胀,部分空泡化,并可见髓鞘样小体,加压３天的筛板细胞合成胶原蛋白,Ｉ,Ⅲ,     

线粒体功能缺陷在遗传性视神经病变发病机制中的作用

线粒体是普遍存在于真核细胞胞质中的一种动态细胞器．其通过氧化磷酸化提供了细胞代谢活动必须的ATP,而且调控细胞凋亡并产生大量的活性氧（reactive oxygen species,ROS）,线粒体DNA突变可导致ATP产量减少而影响细胞的生物能量．然而．绝大部分维持线粒体结构和功能的蛋白质由核基因编码,因此,核基因的突变也可导致细胞能量代谢缺陷。线粒体功能缺陷可引起多种临床疾病,以视觉器官、神经系统及肌肉系统受累为主。视神经对能量缺乏的敏感性较高,因此在线粒体功能异常时最先受累。     

Brain-derived neurotrophic factor released from engineered mesenchymal stem cells attenuates glutamate- and hydrogen peroxide-mediated death of staurosporine-differentiated RGC-5 cells

The purpose of this study was to determine the viability of cell-based delivery of brain-derived neurotrophic factor (BDNF) from genetically modified mesenchymal stem cells (MSCs) for neuroprotection of RGC-5 cells. RGC-5 cells were differentiated with the protein kinase inhibitor staurosporine (SS) and exposed to the cellular stressors glutamate or H₂O₂. As a neuroprotective strategy, these cells were then co-cultured across a membrane insert with mesenchymal stem cells (MSCs) engineered with a lentiviral vector for production of BDNF (BDNF-MSCs). As a positive control, recombinant human BDNF (rhBDNF) was added to stressed RGC-5 cells. After SS-differentiation RGC-5s developed neuronal-like morphologies, and a significant increase in the proportion of RGC-5s immunoreactive for TuJ-1 and Brn3a was observed. Differentiated RGC-5s also had prominent TrkB staining, demonstrating expression of the high-affinity BDNF receptor. Treatment of SS-differentiated RGC-5s with glutamate or H₂O₂, produced significant cell death (56.0 ± 7.02 and 48.90 ± 4.58% of control cells, respectively) compared to carrier-solution treated cells. BDNF-delivery from MSCs preserved more RGC-5 cells after treatment with glutamate (80.0 ± 5.40% cells remaining) than control GFP expressing MSCs (GFP-MSCs, 57.29 ± 1.89%, p < 0.01). BDNF-MSCs also protected more RGC-5s after treatment with H₂O₂ (65.6 ± 3.47%) than GFP-MSCs (46.0 ± 4.20%, p < 0.01). We have shown survival of differentiated RGC-5s is reduced by the cellular stressors glutamate and H₂O₂. Additionally, our results demonstrate that genetically modified BDNF-producing MSCs can enhance survival of stressed RGC-5 cells and therefore, may be effective vehicles to deliver BDNF to retinal ganglion cells affected by disease.     

兔视网膜脱离后视网膜神经节细胞及微血管的形态学观察

目的 观察视网膜脱离( retinal detachment,RD)后视网膜神经节细胞及微血管的形态学变化,以探讨RD后视功能损伤机制.方法 36只青紫兰灰兔左眼经玻璃体内注入透明质酸酶(10U· mL-1)液化玻璃体,抽吸液化玻璃体并以此液流冲击视网膜造成RD模型,右眼作为对照组.根据RD后不同时间分组,分别为RD后6h组、1d组、3d组、7d组、14 d组、28 d组,每组6只兔,每组均于光镜及透射电镜下观察视网膜情况.结果 光镜下观察,与对照组相比,RD后6h组视网膜神经节细胞略肿胀,胞浆着色浅,胞浆中部的Nissl小体消失,仅在细胞周边部有少量残余;1d组视网膜神经节细胞肿胀,神经纤维水肿加重;3 d组视网膜神经节细胞胞周空隙增大,胞体缩小,胞核偏位;7 d组大部分视网膜神经节细胞萎缩、死亡,细胞核固缩;14 d组视网膜神经节细胞数量明显减少;28 d组仪有极少量视网膜神经节细胞存在,神经纤维层明显变薄萎缩.电镜下观察,与对照组相比,视网膜神经节细胞线粒体RD后6h组即出现肿胀,嵴变短;14 d组肿胀线粒体破裂,数量减少;28 d组细胞固缩,难以找到线粒体;RD后视网膜微血管光镜下未见明显改变,但电镜下显示损伤明显.主要表现在基底膜逐渐肿胀、增厚,形态不规则;另外,血管内皮细胞、周细胞内出现空泡,线粒体肿胀、嵴变短甚至空泡样变.结论 随着RD时间的延长,视网膜微血管基底膜逐渐增厚、视网膜神经节细胞缺氧性损伤逐渐加重,可能是RD后视功能损伤机制之一.     

Acute energy reduction induces caspase-dependent apoptosis and activates p53 in retinal ganglion cells (RGC-5)

The energy reduction-induced death of retinal ganglion cells is associated with many ophthalmic diseases. The present study was designed to investigate the apoptosis pathway of retinal ganglion cells (RGC-5) following acute ATP reduction by using glucose deprivation (GD). RGC-5 cells were cultured in glucose-free or normal DMEM for 3 days. The changes in intracellular ATP and cell viability were monitored by ATP assay and MTT assay. APOPercentage™ and in situ TUNEL assays were used to determine the cell death pattern. The involvement of oxidative stress was assessed by measuring intracellular ROS generation, the HO-1 expression, the effect of antioxidants, and the ratio of GSSG to total GSH. The activation of p53 and apoptosis markers was evaluated by Western blotting. We found that glucose deprivation caused an acute decline of intracellular ATP level, concomitantly decreasing cell viability. The cell death exhibited typical features indicative of apoptosis, including cell shrinkage, phosphatidylserine externalization and DNA fragmentation. Oxidative stress was involved in the cell death process; an antioxidant significantly protected the cells against glucose deprivation. p53 and apoptosis markers, caspase-3 and PARP-1 were activated after RGC-5 cells were cultured in glucose-free media for 32 h. Z-VAD-fmk, a pan-caspase inhibitor, was sufficient to prevent apoptosis. These results suggest that acute energy reduction induced by glucose deprivation triggers caspase-dependent apoptosis and activates p53. Blocking the critical steps in this cell death pathway may have therapeutic effects, rescuing the retinal ganglion cells from damages associated with acute energy reduction.     

Mitochondrial dysfunction in glaucomatous degeneration

Glaucoma is a kind of optic neuropathy mainly manifested in the permanent death of retinal ganglion cells (RGCs), atrophy of the optic nerve, and loss of visual ability. The main risk factors for glaucoma consist of the pathological elevation of intraocular pressure (IOP) and aging. Although the mechanism of glaucoma remains an open question, a theory related to mitochondrial dysfunction has been emerging in the last decade. Reactive oxygen species (ROS) from the mitochondrial respiratory chain are abnormally produced as a result of mitochondrial dysfunction. Oxidative stress takes place when the cellular antioxidant system fails to remove excessive ROS promptly. Meanwhile, more and more studies show that there are other common features of mitochondrial dysfunction in glaucoma, including damage of mitochondrial DNA (mtDNA), defective mitochondrial quality control, ATP reduction, and other cellular changes, which are worth summarizing and further exploring. The purpose of this review is to explore mitochondrial dysfunction in the mechanism of glaucomatous optic neuropathy. Based on the mechanism, the existing therapeutic options are summarized, including medications, gene therapy, and red-light therapy, which are promising to provide feasible neuroprotective ideas for the treatment of glaucoma.