The Relationship between Mitochondria and Neurodegeration in the Eye :

Mitochondria are the energy factories of cells. Mitochondrial dysfunction directly affects the  function  and  morphology  of  cells.  In  recent  years,  growing  evidence  has  shown  that mitochondrial dysfunction plays an important role in neurodegenerative diseases. In the eye, some age‐related diseases are considered to be neurodegenerative diseases, such as primary open‐angle glaucoma (POAG) and age‐related macular degeneration (AMD). Here, we review the mechanisms of mitochondrial damage, post‐injury repair, and the roles of mitochondria in various tissues of the eye.  In  the  following  sections,  the  potential  for  treating  glaucoma  by  reducing mitochondrial damage and promoting post‐injury repair is also discussed.


Introduction
Mitochondria are important organelles for the function and survival of retinal cells. Mitochondria are necessary for energy metabolism, the maintenance of redox homeostasis, cell signaling, and the biosynthesis of cell components. Mitochondrial diseases affect almost all aspects of human physiology, and mitochondrial dysfunction plays an important role in neurodegenerative diseases [1]. Mitochondrial DNA damage, oxidative stress, imbalances in ion homeostasis, and mitochondrial autophagy can all lead to mitochondrial dysfunction [2]. There is evidence to support a link between mitochondrial dysfunction and some forms of retinal degeneration. Therefore, we reviewed the mechanisms of mitochondrial damage, post-injury repair, and its potential in the treatment of glaucoma.

Retinal Ganglion Cells (RGCs)
The optic nerve is one of the most energy-demanding nerves in the human body, as well as one of the most oxygen-consuming nerves. Mitochondria provide energy for its normal function. Mitochondrial dysfunction can result in a degeneration of retinal ganglion cells (RGCs) that may lead to glaucoma and various inherited optic neuropathies [3]. When RGCs are subjected to stress, intracellular signaling is modulated, and specific proteins are released into the mitochondrial membrane, leading to mitochondrial damage and RGC dysfunction [4]. neuroinflammation and mitochondrial dysfunction play an important role in the neurodegeneration observed in glaucoma [6]. The function of Müller cells requires high energy production, and some studies suggest that glycolysis is the main energy provider. However, recent studies have highlighted the need for mitochondrial ATP production to support Müller cell function [7]. Many of the structural and functional parameters of mitochondria in senescent Müller cells are impaired by accumulated oxidative damage.

Other Cells of the Inner Retina
The superoxide dismutase (SOD) family is an important antioxidant system, and a deficiency of Cu-and Zn-superoxide dismutase (SOD1) in mice can lead to a variety of phenotypes that are similar to accelerated aging. Some studies have found that, after SOD1 aging, the cells of the inner and outer nuclear cell layers swell and the intracellular mitochondria are degraded. When the activity of manganese superoxide dismutase (MnSOD) and its mRNA expression were decreased, mitochondrial function was impaired, and the inner nuclear layer (INL) was thinned [8][9][10][11]. Reductions in mitochondrial volume and distribution may indicate that retinal ganglion cells in glaucoma are in a state of increased metabolic strain. Genomic analysis revealed that many instances of retinal endometrial cell apoptosis were caused by mutations in mitochondrial genes or nuclear genes encoding mitochondrial proteins [12]. A loss-offunction mutation in the retinal degenerative change 3 (RD3) gene resulted in hereditary retinopathy with impaired rod and cone function. Guanylate-cyclase-activated proteins (GCAPs) may be the key Ca 2+ sensors mediating the physiopathology of this disease. GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. Endoplasmic reticulum stress and mitochondrial swelling are early markers before the death of RD3 retinal photoreceptors [13,14]. OPA1 is a major gene that leads to optic nerve atrophy (DOA). OPA1 encodes dynamin in mitochondria, supports the intimal structure, and is widely expressed [8,9]. The glutamate receptor initiates acute intraocular hypertension, and ischemic injury induces the retinal mitochondria to release OPA1 and activate the cell death pathway, resulting in the apoptosis of inner retinal cells [15][16][17]. A decrease in oxygen consumption (QO2) at the synaptic terminal of the retina and photoreceptors indicates the continued dysfunction of mitochondrial oxidative phosphorylation, the activation of apoptotic pathways, and the apoptosis of retinal endometrium cells [18]. Retinal edema, vacuolation, and the mitochondrial disintegration of retinal cells were observed upon the intravitreal injection of methotrexate in rabbits. After continuous injection, the edema of the photoreceptors and the nucleus and ganglion cell layers were affected, leading to nuclear degeneration in the outer nuclear layer and damage to the photoreceptor layer [19]. Many studies have shown that the overactivation of NMDA receptors leads to a calcium overload in retinal ganglion neurons and defects in the mitochondrial respiratory chain, which promote neurodegenerative diseases, such as glaucoma. Calcium can induce transient hyperpolarization of the mitochondrial membrane potential, trigger the release of reactive oxygen free radicals, and lead to the apoptosis of inner retinal cells [20][21][22]. REEP6 plays an important role in maintaining cGMP homeostasis by promoting the stabilization and/or transportation of guanylate cyclase and maintaining homeostasis in the endoplasmic reticulum and mitochondria; it also plays a protective role in retinal endomyocytes [23]. Nuclear respiratory factor 1 (NRF1) was found to be significantly inhibited by the proliferation of retinal progenitor cells (RPCs) and post-mitotic rod photoreceptor cells (PRSs) in vivo. These results suggest that the NRF1-mediated disruption of mitochondrial biogenesis leads to mitochondrial damage and the slow, progressive degeneration of PRSs in rod cells [24]. The OTX2 (orthodentile homeobox 2) haploid defect leads to various developmental defects in the mammalian visual system, such as retinal dysfunction and the absence of eyes. The OTX2 protein is localized to the mitochondria of bipolar cells and promotes ATP synthesis. As part of the mitochondrial ATP synthase complex, retinal dystrophy in OTX2 +/GFP heterozygous knockout mice was mainly due to bipolar cell loss due to mitochondrial damage [25][26][27].

Impaired Mitochondrial Function in Aging and Glaucoma
Mitochondrial dysfunction can be caused by a variety of factors. Aging, the greatest risk factor for neurodegenerative diseases, is known to correlate with mitochondrial dysfunction [28]. The mitochondrial electron transport chain (ETC) is a very efficient system, but the nature of the alternating one-electron oxidation-reduction reactions predisposes each electron carrier to side reactions with molecular oxygen [29], which result in decreased production of ATP and oxidative overload. This leakage of electrons can be enhanced by exogenous and endogenous impediments, including mitochondrial DNA (mtDNA) mutations, mitochondrial metal dyshomeostasis, and malfunctions in mitochondrial biogenesis and mitophagy. Accumulating evidence suggests that the accumulation of large-scale deletions and mutations in mitochondrial DNA (mtDNA) is involved in the aging process [28,30,31]. Nonetheless, mitochondrial dysfunction can also be secondary to glaucomatous pathogenic factors, such as elevated mechanic stress and insufficient retinal perfusion, which consequently lead to diminished oxidative substrates, disrupted mitochondrial biogenesis, and insults to the electron transport chain [30][31][32], thus contributing to reduced energy availability, an increased net production of reactive oxygen species (ROS), the accumulation of damaged mitochondria, and the activation of apoptosis [33,34].

How Aging Affects Mitochondrial Function
Genomic instability in mitochondria is one of the contributing factors for age-related retinal pathophysiology [35]. Mitochondria have their own circular mtDNA, which is ~16.5 kb. The mtDNA lacks protective proteins, such as histone and non-histone proteins, and its structure makes it extremely vulnerable to oxidative damage [36]. ROS damage and mtDNA mutations form a vicious cycle and promote each other. It is a significant phenomenon that retrograde communication can increase oxidative mtDNA damage [37]. With an increase in age, the mitochondrial DNA oxidation level increases, which affects the transcription and replication of mitochondrial DNA and further changes the functions of mitochondrial proteins [38]. Mitochondrial stress response pathways can regulate the aging process [39]. As they provide energy to cells, mitochondria lead to increased levels of reactive oxygen species and oxidative stress products; this process is one of the main drivers of aging [40]. Declines in mitochondrial quality and activity affect not only normal aging, but also a range of age-related diseases [41]. Mitochondrial dysfunction and altered mitochondrial dynamics are some of the main causes of aging and age-related diseases [42]. Mitochondrial autophagy is a special form of autophagy that regulates mitochondrial dysfunction and damage. Reduced mitochondrial autophagy and phagocytosis play an important role in neurodegenerative diseases [43] (Figure 1).
The inner mitochondrial membrane is the main source of superoxide, which can produce a large amount of hydrogen peroxide (H2O2), which can further react to form a hydroxyl radical (HO•). The outer mitochondrial membrane can catalyze the oxidation and deamination of biogenic amines and is the source of a large quantity of H2O2. These toxic reactions significantly contribute to the aging process and form the central tenet of the "free radical theory of aging". The mtDNA is a key cellular target for ROS, and the chronic ROS exposure found in several aging-related degenerative diseases leads to decreased mitochondrial function, increased mitochondrial production of ROS, and persistent mitochondrial DNA damage. Polγ has been identified as one of the major oxidative mitochondrial matrix proteins. As a target for oxidative damage, Polγ can partially damage mitochondrial function by increasing oxidative stress, ultimately leading to a reduction in mitochondrial DNA replication and repair ability [44,45].
Previous studies have found that ROS production in cells can be regulated by regulating mitochondrial activity. Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and reduces the mitochondrial damage mediated by reactive oxygen species [46,47]. The mitochondrial electron transport chain is a highly efficient multifunctional system that can oxidize one glucose molecule to produce 38 ATP molecules. Mitochondrial electron transport chains can produce side reactions, such as those for superoxide anion radicals (O 2 •) and hydroxyl radicals (HO•), resulting in reduced production of ATP and oxidative overload. Studies have confirmed that, in mitochondrial DNA, mitochondrial autophagy, mutations, biological failure which can be defined as the inadequacy of the host tissue to establish or to maintain, abnormal metal homeostasis, and other factors lead to electron leakage in the mitochondrial electron transport chain [48]. In past clinical trials, the non-specific elimination of ROS through the use of low molecular antioxidant compounds was not successful in inhibiting the occurrence and progression of disease. However, selectively targeting specific ROSmediated signaling pathways offers a prospect for more sophisticated REDOX drugs in the future. This includes enzymatic defense systems, such as those controlled by the stress response transcription factors Nrf2 and nuclear factor κB, the roles of trace elements, such as selenium, the use of REDOX drugs, and the regulation of environmental factors, which are collectively referred to as exposures [49]. The high mitochondrial membrane potential generated by hyperglycemic electron donors may cross the mitochondrial membrane in the TCA cycle. Electron transport is blocked, resulting in the reduction of O2 into superoxide [50]. Increasing ROS leads to enhanced lipid peroxidation and the oxidative modification of proteins in mitochondria, thus further aggravating mtDNA mutations and oxidative damage in the aging process. The impairment of electron transport function leads to increased electron leakage and ROS production, leading to increased oxidative stress and oxidative damage in mitochondria [36]. Mitochondrial electron transfer chains have alternative redox reactions, which evolve to produce pro-apoptotic ROS in response to specific stress signals [51]. p66Shc is an oxidoreductase that produces mitochondrial ROS (hydrogen peroxide) through the oxidation of cytochrome C, which acts as a signaling molecule. Some studies have found that MEV-1 may cause an increase in superoxide levels in nematodes. The ability of complex II to catalyze electron transfer from succinate to ubiquinone is impaired. This can lead to an indirect increase in superoxide levels, which, in turn, can lead to peroxidation and premature aging. MEV-1 regulates the rate of aging by regulating cellular responses to oxidative stress for apoptosis [52], [53].
The electron transport chain complex inhibitor II can block the production of ROS [54]. The selective S-nitrosation of Cys39 on the ND3 subunit may block complex I, thereby reducing the production of ROS [55]. The mitochondrial uncoupling protein can reduce the efficiency of oxidative phosphorylation and then participate in the control of mitochondrial reactive oxygen production [56]. In mitochondrial metabolism, oxidative stress leads to the intermittent transmission of mitochondrial signals, which plays an important role in cell energy [57]. In the study of the relationship between mitochondrial functional damage and aging, early studies suggested that oxidative damage was the cause of mtDNA mutations, while recent studies have demonstrated that replication errors by mtDNA polymerase are the main cause of mtDNA mutations [58]. Calciumactivated mitochondrial nucleases cause mitochondrial DNA, RNA, and proteins to be modified through oxidative stress. Oxidative-stress-induced apoptosis involves the early degradation of mitochondrial polynucleotides (including DNA and RNA), a process that occurs prior to the nuclear DNA "ladder" [48]. Insoluble Tau aggregates merge into the membrane, change the ionic current, change the plasma membrane potential, and activate VGCCs, which, in turn, induce calcium influx and trigger the production of ROS in NADPH oxidase, leading to neuronal cell death [48]. The prolongation of the transient duration of Ca 2+ leads to Ca 2+ overload, which promotes cell death [59,60]. The mitochondrial permeability transition (MPT) is a phenomenon of a sudden increase in the permeability of the inner mitochondrial membrane caused by excessive calcium accumulation and/or oxidative stress. It is generally believed that the MPT consists of a large channel (up to 1.5 kDa) that allows ions and small molecules to pass through the intima. The activation of the MPT leads to the depolarization of the mitochondrial membrane and loss of mitochondrial function, leading to the core event of mitochondrial dysfunction [61]. Under the condition of pathological calcium overload, the disappearance of polyps leads to a significant decrease in the mitochondrial free calcium concentration. Inorganic polyP can inhibit the precipitation of calcium phosphate, thus increasing the amount of free calcium [62]. Mitochondria regulate the innate immune system and influence the rate of aging [63]. Mitochondrial damage can lead to a decline in myocardial cell function, which is one of the important factors for the structural and functional changes in aging hearts [64]. Oxidative damage in the mitochondria leads to a decrease in the NADPH pool and accelerates the aging process [65]. Some studies have found that the RNA-binding protein pumiliO2 (PUM2) is a translation inhibitor and that PUM2 inhibits the mitochondrial fission factor (MFF) to inhibit mitochondrial fission and mitochondrial phagocytosis, thus playing a role in the regulation of aging [66]. Mitochondria are involved in key central metabolic pathways and regulate a variety of cellular functions, so it is not surprising that structural defects and dysfunctions in mitochondria affect aging [67]. ROS are the most important endogenous cause of mtDNA damage, and they lead to mtDNA damage that is more extensive than nuclear DNA damage [37]. Other toxic chemicals, such as alkylating agents, can modify mtDNA to a greater extent than they can nuclear DNA, so they cause serious mtDNA damage [3]. Mitochondrial DNA (mtDNA) is not protected by histones or DNA-binding proteins and is continuously exposed to high homeostatic levels of ROS and free radicals in the mitochondrial matrix. Therefore, mtDNA is prone to oxidative modification and mutation, and the degree of the oxidative modification and mutation of mitochondrial DNA increases exponentially with age. In mtDNA diseases, truncated or incorrect mitochondrial polypeptides are produced, and these may be incorporated into oxidative phosphorylation complexes. This causes the production of defective oxidative phosphorylation complexes that can accumulate if they are not rapidly turned over. In addition, the inability to correctly assemble functioning mitochondria may lead to an upregulation of the production of many mitochondrial polypeptides or increase the biogenesis of the whole organelle in an attempt to compensate for an energy deficit [59]. The sensitivity of mitochondrial DNA to damage by mutagens predisposes mitochondria to injury upon the exposure of cells to genotoxins or oxidative stress. Damage to the mitochondrial genome that causes mutations or loss of mitochondrial gene products, as well as damage to some nuclear genes that encode mitochondrial membrane proteins, may accelerate the release of reactive species of oxygen. Such aberrant mitochondria may contribute to cellular aging and the promotion of cancer [68]. ND5 (ND5 gene) is involved in the proton pump mechanism. Thus, mutations in ND5 may inhibit the activity of complex I, leading to oxidative stress [69]. Some studies have suggested that mtDNA polymerase γ has an inherent error rate, which may contribute to mtDNA mutations. The mtDNA mutations that are accumulated cause the formation of a mosaic electron transport chain deficiency in aging humans [70].

How Elevated Intraocular Pressure (IOP) Affects Mitochondrial Function
Mitochondrial autophagy is a type of mitochondrion-specific autophagy, which is an important part of mitochondrial quality control and a collective mechanism that is responsible for the homeostasis of this organelle [71]. The activation of autophagy occurs before the process of apoptosis and is partly mediated by reactive oxygen species and the formation of mitochondrial permeability transition pores. The formation of mitochondrial permeability transition pores is directly related to the autophagy induced by 3NP treatment [72]. Phosphorylated ubiquitin may act as a receptor. After effectively stabilizing and activating OMM, parkin ubiquitinates a large number of OMM proteins, which, in turn, attract specific autophagy receptors, thus triggering autophagy. AMP activates protein kinase (AMPK), insulin-like signaling (ILS) pathways, and the signaling cascades triggered by calcium and nitric oxide, which, in turn, lead to mitochondrial protein folding; these proteins are directed to different mitochondrial sub-compartments depending on the folded sequence: the outer mitochondrial membrane (OMM), intermembrane space (IMS), inner mitochondrial membrane (IMM), or matrix [73]. TFEB is activated after mitochondrial autophagy in order to maintain the ALP and mitochondrial biogenesis. The level of PGC-1α (peroxisome proliferator-activated receptorγcoactivator-1, PGC-1) mRNA in cells with increased TFEB protein is significantly increased. PGC-1α mRNA is a regulator of mitochondrial biogenesis and leads to increased mitochondrial content [74]. Elevated intraocular pressure (IOP) can affect mitochondrial division, induce the release of optic atrophy type 1 (OPA1), and directly damage the optic nerve head (ONH) axons [75][76][77]. Inhibitory glutamate receptor activation inhibits the release of OPA1 in mitochondria induced by acute IOP elevation; thus, glutamate receptors' activation of acute IOP elevation may lead to mitochondrionmediated cell death pathways in the ischemic retina [17,78] (Figure 2). Increased mitochondrial OPA1 may provide an important cellular defense mechanism against stress-mediated retinal damage [79]. Some studies have shown that the early modulation of gene expression changes the retinal ganglion cell layer (GCL) in mouse models of glaucoma. Genes downregulated in the mitochondria are involved in the metabolic pathway and influence retinal ganglion cells [80]. Neuroglobin (NGB) is a newly discovered member of the globulin superfamily. As an endogenous neuroprotectant, it can reduce oxidative stress and improve mitochondrial function, thus promoting the survival of RGCs [81,82]. It was found that p62 was present in the mitochondria of retinal ganglion cells (RGC-5), and large amounts of nicotinamide mononucleotide adenylyl transferase 3 (Nmnat3) and p62 were co-localized in the mitochondria. Nmnat3 transfection can reduce the p62 of RGC-5 cells and increase autophagic flux. The regulation of Nmnat3 and autophagy may induce optic neurodegenerative diseases [83]. Elevated acute IOP significantly increases the expression of the retinal mitochondrial transcription factor A (TFAM) protein, which regulates the copy number and transcriptional activity of mitochondrial DNA, participates in cell apoptosis, and affects the axonal regeneration of the optic nerve [84]. Dynamic changes in mitochondria (MT) induced by elevated intraocular pressure are involved in the occurrence and development of neurodegenerative diseases. In a glaucoma mouse model (DBA/2J (D2)), DRP1 (dynamin-related protein 1) inhibition promoted RGC survival by increasing the phosphorylation of BAD (B lymphoma-2 gene related promoter) at serine 112 in the retina. The RGCs' axons are preserved by the maintenance of the integrity of the MT of the glial layer [85][86][87]. Progressive swelling of the mitochondria following elevated intraocular pressure causes severe structural changes, leading to the death of RGCs [88][89][90]. Elevated intraocular pressure causes mitochondrial damage and mutations, leading to the progressive loss of RGCs [6,91]. Chronic hypertension can change the morphology and function of retinal ganglion cell mitochondria [92][93][94][95], and mitochondrial activity is also affected [96][97][98]. The pathogenesis of many neurodegenerative changes is related to disorders of mitochondrial metal homeostasis. The Zn in mitochondria is released into the cytoplasm, resulting in an imbalance of Zn 2+ , which, in turn, leads to the production of superoxide and affects cell function [99]. Zn and Cu belong to superoxide dismutase 1 (SOD1) of the mitochondrial IMS and have important antioxidant functions [100]. Copper plays an important role in maintaining the function of antioxidant enzymes [56]. Mitochondria contain a Cu antioxidant protein. If CCS overexpression promotes Cu transport to SOD1, it will increase the aggregation of mitochondrial SOD1G93A, leading to cytotoxicity in neuronal cells [101]. Zinc binds to enzymes that block the mitochondrial absorption of SOD1 [100]. Relationship between elevated intraocular pressure and mitochondrial dysfunction. Elevated IOP caused mitochondrial electron transport chain dysfunction, mitochondrial genome alterations and metal dyshomeostasis, leading to mitochondrial dysfunction that increased ROS and decreased ATP which can give rise to axon damage of RGCs.

Markers of Impaired Mitochondrial Function in Glaucoma Patients
Deletions in mtDNA were dramatically increased in the trabecular meshwork of primary open-angle glaucoma (POAG) patients [102], and mitochondrial dysfunction was detected in primary TM cultures collected from POAG patients [103]. Reduced mitochondrial respiration due to complex-I impairments was observed in almost 90% of POAG patients [104]. A study using whole-mitochondrial-genome sequencing detected pathogenic mitochondrial DNA mutations in 50% of the POAG cohort, and 36% of the mutations were in one of the complex-I mitochondrial genes [105]. Furthermore, significantly lower rates of complex-I-driven ATP synthesis and respiration were observed in the lymphoblasts of POAG patients [106]. Activity specific to complex-I enzymes was reduced by 18% in POAG lymphoblasts, and complex-I ATP synthesis decreased by 19% in POAG patients [107].

How Reduced ATP Plays a Role in Glaucoma
The pharmacologic responsiveness of ATP was reduced in surviving cells with elevated intraocular pressure [108]. Reduced ATP production impairs the growth and development of the trabecular meshwork (TM), ultimately leading to elevated intraocular pressure and the death of RGCs [31,107,[109][110][111]. Several studies have shown that a similar release of ATP was measured in human-explant-derived primary trabecular mesh (TM) cells (HTMs) and human TM cell lines (TM5), and that ionizing mycin can trigger ATP release and regulate apoptosis [112][113][114][115]. The levels of ATP in the blood and aqueous humor of glaucoma patients were significantly lower than those in the control group [116]. The ATP released by the retinal glia protects retinal ganglion cells by stimulating the A1 and A3 adenosine receptors to convert into adenosine. By contrast, the stimulation of the P2 × 7 ATP receptor kills retinal ganglion cells in vivo and in vitro [117][118][119][120]. In glaucoma, the mitochondrial surface area of elderly DBA/2J axons and the ability to produce ATP are reduced, leading to insufficient energy in the optic nerve and causing irreversible damage [121][122][123]. The structural changes in aging mitochondria and the decrease in the ATP level are some of the most important causes of cell death in neurodegenerative diseases [124][125][126][127].

How Increased Reactive Oxygen Species (ROS) Play a Role in Glaucoma
Oxidative stress plays an important role in the pathogenesis of primary glaucoma. Pro370Leu-mutant myocardial protein can induce mitochondrial dysfunction and produce increased reactive oxygen species, leading to the induction of glaucoma [128]. The active form of phosphorylated NF-κB (pNF-κB) increases oxidative stress levels and inhibits neurite growth in RGCs [129]. Fe and Mn can remove superoxides in vivo and in vitro, and they have a neuroprotective effect on neurons [130]. The production of ROS in lysosomes induces lysosomal membrane permeability and the release of cathepsin D into the cytoplasm, leading to the death of TM cells and inducing the pathogenesis of glaucoma [131][132][133][134][135][136][137][138][139]. Increased ROS-generated death signals can cause RGC injuries and glaucoma [140][141][142]. The superoxide ROS are thought to be key signals that cause the death of RGCs after axonal injuries. However, the chemical reduction of oxidized sulfhydryl groups has been shown to have neuroprotective effects on injured RGCs [7,[143][144][145][146][147][148][149]. Bis (methyl 3-propionate) phenylphosphonborane complex 1 (PB1) protects the impaired RGCs by activating survival signaling [150]. In glaucoma, oxidative stress and mitochondrial dysfunction in glaucomatous cells are involved in pathological changes in the optic nerve head [151][152][153]. The retinal ganglion cell layer, including the blood vessels, shows increased ROS levels. Hydrogen sulfide (H2S) is a newly discovered gas signaling molecule that regulates the oxidative stress response and plays a role in the regulation of oxidative stress in glaucoma, By removing reactive oxygen species and dilating retinal blood vessels, H2S can protect retinal ganglion cells from death caused by stress and oxidative stress in vitro and in vivo [149,154]. The expression of NADPH oxidase subtype NOX2 and inflammatory cytokine TNF-α in retinal tissue is increased at the mRNA level. Elevated intraocular pressure impairs the automatic regulation of retinal arterioles and induces oxidative stress in mice [155][156][157].

Potential Glaucoma Treatments Targeting Mitochondria
Mitochondria have been shown to play an important role in age-related neurodegenerative diseases. Mitochondria are key regulators of cell death and are a key feature of neurodegeneration. Mitochondrial DNA mutations and oxidative stress both contribute to aging, which is the biggest risk factor for neurodegenerative diseases. In addition, many disease-specific proteins interact with mitochondria. Therapies that target fundamental mitochondrial processes, such as energy metabolism or free radical generation, or specific interactions of disease-associated proteins with mitochondria therefore have potential significance [34]. Mitochondrial autophagy is a type of mitochondrion-specific autophagy. Large amounts of ROS, DNA damage, and excessive energy consumption during retinal senescence all lead to the degeneration of RPE cells and their mitochondria. The restoration of mitochondrial quality and activity plays a role in anti-aging therapy. A better understanding of mitochondrial autophagy is crucial for finding treatments effective against age-related degenerative diseases, such as primary open-angle glaucoma [71]. The free radical scavengers TEMPOL (a superoxide dismutase analog) and MnTBAP (manganese porphyrin) inhibit 6-OHDA-induced autophagy activation. They have a protective effect on mitochondria [158]. Adenosine A2A (Adensone A2A) receptor (A2AR) stimulation enhances mitochondrial metabolism and reduces the mitochondrial damage mediated by reactive oxygen species [47]. Selectively targeting specific ROS-mediated signaling pathways offers a prospect for more sophisticated redox drugs in the future. These include the enzyme defense system, the roles of trace elements, the use of redox drugs, and environmental factors [159]. Mitochondrial damage is a common mechanism of cell death in neurodegenerative diseases. Therefore, mitochondrial protection and mitochondrial repair are effective ways to protect retinal nerves. Peroxisome-proliferator-activated receptor γ-coactivators α (PGC-1α) and β (PGC-1β) are transcriptional coactivators and are the major regulatory factors of mitochondrial biogenesis. They may play a key role in the regulation of retinal cell survival and may be an important therapeutic target for the prevention of optic neurodegenerative diseases [160]. Mitochondrial dysfunction is involved in the pathogenesis of AMD (age-related macular degeneration) and POAG, and these diseases accumulate mitochondrial defects in different cell types that ultimately affect the entire neural retina. Given the central role of mitochondria in cell homeostasis, proliferation, and death, strategies targeting mitochondria may have potential for treatment of POAG [161]. Glaucoma is increasingly recognized as a neurodegenerative disease, and there is much evidence that mitochondrial defects contribute to the pathogenesis of glaucoma. Viewing glaucoma as a mitochondrial neurodegenerative disease opens up new avenues for treatment based on increased mitochondrial protection or improved quality control of the mitochondrial life cycle. The optic nerve is one of the nerves with the largest energy demands and the highest oxygen consumption. As mitochondria provide energy for the optic nerve, mitochondrial dysfunction may lead to glaucoma, so the treatment of mitochondrial dysfunction may become a new intervention target [3]. Mitochondrial dysfunction may be a risk factor for POAG. This concept could lead to new experimental and therapeutic opportunities [104]. Mitochondrial involvement in the pathogenesis of glaucoma provides a new strategy for the protection of the optic nerve and the prevention of vision loss. Therefore, SKQ1 may be a candidate drug for the treatment of glaucoma. The dysfunction of calcium regulation causes the tissue to be unable to control intraocular pressure. Drug inhibitors of IP3R, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) opening, and cyclophilin D may have clinical significance for primary open-angle glaucoma [103].

Conclusions
In summary, mitochondria provide energy for cells, and mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases. Because the inner cells of the retina contain large numbers of mitochondria and rely on mitochondria to provide energy in order to maintain cellular function, the study of the mechanisms of mitochondrial damage may provide potential strategies for the treatment of glaucoma. However, there are still several unanswered questions to be addressed, and the complex structure of the retina makes it unclear how metabolic defects in a single cell affect the health of neighboring cells. At present, there are few studies on the mitochondria of RGCs, and there is still much work to be done to be able to infer the mechanisms of human retinal injury from the data of animal models of glaucoma. The road to regulatory approval for experimental drugs for treating mitochondria remains long and arduous.

Conflicts of Interest:
The authors declare no conflict of interest.