Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury
- 1.8k Downloads
Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.
KeywordsCoenzyme Q10 Retinal ischemia Retinal ganglion cell Oxidative stress Mitochondrial transcription factor A Mitochondrial DNA
Elevated intraocular pressure (IOP) is an important risk factor for retinal ganglion cell (RGC) death and optic nerve degeneration in retinal ischemia and glaucoma . Growing evidence indicates that ischemic injury by acute IOP elevation alters mitochondrial dynamics-related proteins and induces mitochondrial dysfunction-mediated apoptotic cell death in the retina of rodent models [2, 3]. Importantly, our previous studies demonstrated that IOP elevation triggered release of mitochondrial fusion protein optic atrophy 1 and increase of mitochondrial fission GTPase dynamin related protein-1, as well as induced apoptotic cell death by modulating Bax/phosphorylated Bad (pBad) protein expression in ischemic retina [2, 3]. Collectively, these findings suggest that ischemic injury induced by acute IOP elevation is associated with mitochondrial dysfunction-mediated apoptotic pathway in the retina.
Oxidative stress has been implicated as an important pathophysiological mechanism for mitochondrial dysfunction-mediated retinal neurodegeneration including ischemic injury [4, 5, 6, 7]. Superoxide dismutases (SODs), cytosolic SOD1 and mitochondrial SOD2, are expressed in the ganglion cell layer (GCL) and inner plexiform layer in rodent retina . A recent study suggests that SOD2 has a protective role against oxidative stress-mediated neuronal cell death . Of interest, we found that acute IOP elevation significantly increased SOD2 protein expression in the early neurodegeneration of ischemic rat retina . In addition, increasing evidence indicates that oxidative stress is associated with mitochondrial DNA (mtDNA) alteration-related mitochondrial dysfunction in retinal neurodegeneration [5, 7, 10, 11]. However, it remains unknown whether oxidative stress induced by acute IOP elevation causes mtDNA alteration in ischemic retinal injury.
Mitochondrial transcription factor A (Tfam, also as known as mtTFA), a nucleus encoded DNA-binding protein in mitochondria, has an important role in mitochondrial gene expression and mtDNA maintenance, and therefore is essential for oxidative phosphorylation (OXPHOS)-mediated adenosine triphosphate (ATP) synthesis [12, 13, 14, 15]. Mice lacking Tfam have impaired mtDNA transcription and loss of mtDNA leads to bioenergetics dysfunction and embryonic lethality . In contrast, overexpression of Tfam mediates delayed neuronal death following transient forebrain ischemia in mice [16, 17, 18] as well as neonatal hypoxic-ischemic brain injury rapidly increased Tfam and OXPHOS complex IV protein expression in a rat model . This suggests that these responses may support endogenous repair mechanisms for mtDNA damage following hypoxic-ischemic brain injury . Of note, acute IOP elevation significantly increased Tfam and OXPHOS complex protein expression in the early neurodegeneration of ischemic rat retina , collectively suggesting that these responses may reflect endogenous repair mechanisms for elevated IOP-induced mitochondrial alteration in ischemic injury.
Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, acts by maintaining the mitochondrial membrane potential, supporting ATP synthesis and inhibiting reactive oxygen species (ROS) generation for protecting neuronal cells against oxidative stress in neurodegenerative diseases [20, 21, 22]. Previous studies have demonstrated that CoQ10 protected retinal neurons against hydrogen peroxide-induced oxidative stress in vitro  as well as prevented retinal damage caused by acute high IOP-induced transient ischemic injury [24, 25].
In the current study, we tested whether a diet supplemented with CoQ10 ameliorates oxidative stress-mediated apoptotic cell death in RGC degeneration by preventing mitochondrial alteration in ischemic mouse retina.
Materials and methods
Female, 4-month-old C57BL/6 mice (20–25 g in weight; The Jackson Laboratories, Bar Harbor, ME, USA) were housed in covered cages, fed with a standard rodent diet ad libitum, and kept on a 12 h light/12 h dark cycle. All procedures concerning animals were performed in accordance with the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and under protocols approved by institutional IACUC committees at the University of California San Diego.
Induction of transient retinal ischemia
The mice were anesthetized with a mixture of ketamine (100 mg/kg, Ketaset; Fort Dodge Animal Health, Fort Dodge, IA, USA) and xylazine (9 mg/kg, TranquiVed; Vedeco, Inc., St. Joseph, MO, USA) by intraperitoneal (IP) injection. Eyes were also treated with 1 % proparacaine drops. A 30-gauge needle was inserted into the anterior chamber of right eye that was connected by flexible tubing to a saline reservoir. By raising the reservoir, IOP was elevated to 70–80 mmHg for 50 min. Sham treatment was performed in the contralateral eyes by the insertion of a needle in the anterior chamber without saline injection. Retinal ischemia was confirmed by observing whitening of the iris and loss of the retina red reflex. IOP was measured with a tonometer (TonoLab; Tiolatoy, Helsinki, Finland) during ischemia. Non-ischemic contralateral control retinas were used as control.
CoQ10 was purchased from Kaneka Nutrients (Pasadena, TX, USA) or Sigma (St. Louis, MO, USA). AIN-93G purified control or a diet supplemented with CoQ10 were formulated by Harlan Laboratories (Madison, WI, USA). Four groups of mice were studied: a group of non-ischemic C57BL/6 mice treated with control diet (n = 20 mice), a group of ischemic C57BL/6 mice treated with control diet (n = 30 mice), a group of non-ischemic C57BL/6 mice treated with 1 % CoQ10 diet [(v/v), which equals a daily dose of 1,600–2,000 mg/kg body weight in 25–30 g mice, n = 20 mice]  and a group of ischemic C57BL/6 mice treated with 1 % CoQ10 diet (n = 30 mice).
Six to 24 h after acute IOP elevation, light adapted mice were anesthetized with IP injection of mixture of ketamine/xylazine, as described, and then mice were perfused transcardially with 0.9 % saline followed by 4 % paraformaldehyde in 1X phosphate buffer saline (PBS, pH 7.4). Both eyes enucleated and fixed in 4 % paraformaldehyde in PBS for 4 h at 4 °C. After several washes in PBS, the retinas were dissected and then dehydrated through graded ethanol solutions and embedded in polyester wax, as described previously .
Whole-mount immunohistochemical analysis
Retinas from enucleated eyes were dissected as flattened whole-mounts at 12 h or 2 weeks after ischemia–reperfusion. Retinas were immersed in PBS containing 30 % sucrose for 24 h at 4 °C. The retinas were blocked in PBS containing 3 % donkey serum, 1 % bovine serum albumin, 1 % fish gel and 0.1 % Triton X-100 for 1 h, and incubated with goat polyclonal anti-Brn3a antibody (1:500; Santa Cruz Biotechnology, Santa Cruz, CA, USA), a specific maker for RGCs [28, 29], and guinea pig polyclonal anti-GFAP antibody (1:500; Advanced ImmunoChemical, Long Beach, CA, USA) for 3 days at 4 °C. After several wash steps, the retinas were incubated with the secondary antibodies, Alexa Fluor-568 donkey anti-goat IgG antibody or Cy5-conjugated anti-guinea pig IgG antibody (Invitrogen, Carlsbad, CA, USA) for 24 h, and subsequently washed with PBS. The retinas were counterstained with the nucleic acid stain Hoechst 33342 (1 μg/mL; Invitrogen) in PBS. Images were captured under fluorescence microscopy (Eclipse microscope, model E800; Nikon instruments Inc., Meliville, NY, USA) equipped with a digital camera (SPOT; Diagnostic Instrument, Sterling Heights, MI, USA). Images were acquired with commercial software (Simple PCI version 6.0 software; Compix Inc., Cranberry Township, PA, USA).
Quantitative analysis for RGC counting
To count RGCs labeled with Brn3a, each retinal quadrant was divided into three zones by central, middle, and peripheral retina [one sixth (~400 μm), three sixths (~1,200 μm), and five sixths (~2,000 μm) of the retinal radius from the optic nerve head]. Images were taken at 20×, covering an area of 0.344 mm2, and then the number of RGCs were normalized per mm2. RGC densities were measured in 24 distinct areas (two areas at central, middle, and peripheral per retinal quadrant) per condition by two investigators in a masked fashion, and the scores were averaged (n = 7 retinas/group). To further examine RGC survival between control and CoQ10 diet-treated non-ischemic retinas, RGC densities were automatically measured using ImageJ cell counting analysis (http://rsb.info.nih.gov/ij/, National Institute of Health, Bethesda, MD, USA).
Immunohistochemical staining of retinal cross sections at 12 h after transient ischemia was performed as previously described . Five sections per wax block from each group were used for immunohistochemical analysis. Primary antibodies were goat polyclonal anti-Brn3a antibody (1:500; Santa Cruz Biotechnology, Santa Cruz, CA, USA), a specific maker for RGCs , monoclonal mouse anti-GFAP antibody (1:500; Sigma, St. Louis, MO, USA) and rabbit polyclonal anti-Iba1 antibody (1:500; Wako Chemicals USA, Inc., Richmond, VA, USA). To prevent non-specific background, tissues were incubated in 1 % bovine serum albumin/PBS for 1 h at room temperature before incubation with the primary antibodies for 16 h at 4 °C. After several wash steps, the tissues were incubated with the secondary antibodies, Alexa Fluor 568 dye-conjugated donkey anti-goat IgG antibody (Invitrogen, Carlsbad, CA, USA), Cy5 dye-conjugated goat anti-mouse IgG antibody (Invitrogen) or Alexa Fluor 488 dye-conjugated anti-rabbit IgG antibody (1:100; Invitrogen) for 4 h at 4 °C and subsequently washed with PBS. The sections were counterstained with the nucleic acid stain Hoechst 33342 (Invitrogen) in PBS. Images were acquired with confocal microscopy (Olympus FluoView1000; Olympus, Tokyo, Japan).
Western blot analysis
Following 6, 12 or 24 h after transient ischemia, the collected retinas were homogenized in a glass-Teflon Potter homogenizer in RIPA lysis buffer (150 mM NaCl, 1 mM EDTA, 1 % NP-40, 0.1 % SDS, 1 mM DTT, 0.5 % sodium deoxycholate and 50 mM Tris-Cl, pH 7.6) containing complete protease inhibitors (Roche Biochemicals, Indianapolis, IN, USA). Each sample (10 μg; n = 3 retinas/group) was separated by PAGE and electrotransferred to polyvinylidenedifluoride membrane. The membrane was blocked with 5 % nonfat dry milk and 0.1 % Tween-20 in PBS for 1 h, incubated with rabbit polyclonal anti-SOD2 antibody (1:5000; Santa Cruz Biotechnology), rabbit polyclonal anti-HO-1 antibody (1:1000; Millipore), monoclonal mouse anti-GFAP (1:3000; Sigma), rabbit polyclonal anti-Iba-1 antibody (1:2000; Wako Chemical USA), mouse monoclonal anti-caspase antibody (1:3000; Cell Signaling, Danvers, MA, USA), rabbit polyclonal anti-Bax antibody (1:500; Santa Cruz Biotechnology), mouse monoclonal anti-phosphorylated Bad (pBad, 1:2000; Cell Signaling), goat polyclonal anti-Tfam antibody (1:1000; Santa Cruz Biotechnology), rabbit polyclonal anti-Porin (1:1000; Calbiochem, La Jolla, CA, USA) and mouse monoclonal anti-actin antibody (1:10,000, Millipore, Billerics, MA, USA) for overnight at 4 °C. After several washes in Tween/PBS, the membranes were incubated with peroxidase-conjugated donkey anti-goat IgG (1:5000: Bio-Rad, Hercules, CA, USA), goat anti-rabbit IgG (1:5000; Bio-Rad) or goat anti-mouse IgG (1:5000; Bio-Rad), and developed using chemiluminescence detection (ECL Plus; GE Healthcare Bio-Science, Piscataway, NJ, USA). The scanned film Images were analysed by ImageJ (National Institute of Health) and band densities were normalized to the band densities for actin or porin.
The retinal cross sections at 12 h after transient ischemia were incubated with proteinase K (10 μg/mL, 10 mM Tris, pH 7.4–8.0) for 10 min at 37 °C. After rinsing in PBS, the sections were incubated with terminal deoxynucleotidyl transferase plus nucleotide mixture in reaction buffer for 60 min at 37 °C (In situ Cell Death Detection kit, Roche Applied Science, Indianapolis, IN, USA) as previously described . To count TUNEL-positive cells, the areas were divided into three layers by GCL, inner nuclear layer (INL) and outer nuclear layer (ONL). TUNEL-positive cells were counted in eight microscopic fields of 0.2 mm from retinal sections per condition (n = 5 retinas/group) by two investigators in a masked fashion, and the scores were averaged.
Measurement of mtDNA content
MtDNA content of each sample at 12 h after transient ischemia was determined as described previously . Briefly, total genomic DNA (gDNA) was isolated from retinas by using DNeasy® Blood & Tissue Kit (Qiagen, Valencia, CA, USA) as described in the manufacturer’s protocol. For the measurement of relative mtDNA content, real-time PCR was carried out using MX3000P real-time PCR system (Stratagene, La Jolla, CA, USA) as following. Total gDNAs (10 ng) from the each sample were amplified using iQTM SYBR® Green supermix (Bio-Rad, Hercules, CA, USA) and mitochondrial cytocrome B (CytB-F: 5′-GGTCTTTTCTTAGCCATACACTACA-3′; CytB-R: 5′-ATATCGGATTAGTCACCCGTAAT-3′) or β-actin (ActB-F; GATCGATGCCGGTGCTAAGA-3′; ActB-R: 5′-CACCATCACACCCTGTGGAAG-3′) primers for 40 cycles [initial incubation at 95 °C for 10 min, and 40 cycles (95 °C for 30 s, 55 °C for 30 s and 72 °C for 20 s)]. Output data were obtained as Ct values and the difference of mtDNA content among samples was calculated using the comparative Ct method . ActB gene was used to normalize the ratio between mtDNA and gDNA. The samples were run in triplicates for all experiment.
Data were presented as the mean ± SD. Comparison of two or three experimental conditions was evaluated using the unpaired, two-tailed Student’s t test or one-way analysis of variance and the Bonferroni t test. P < 0.05 was considered to be statistically significant.
The effect of CoQ10 in IOP and body weight
CoQ10 ameliorates oxidative stress in ischemic retina
CoQ10 promotes RGC survival in ischemic retina
CoQ10 blocks apoptotic cell death by decreasing Bax or by increasing pBad protein expression in ischemic retina
CoQ10 preserves Tfam protein expression in ischemic retina
CoQ10 is an attractive neurotherapeutic agent for retinal protection against high IOP elevation-induced oxidative stress in retinal ischemic injury [24, 25] as well as other neurodegenerative diseases including Parkinson’ and Huntington’s diseases [20, 26, 40, 41, 42]. Moreover, CoQ10 is neuroprotective in retinal cells in vivo and in vitro against oxidative stress and excitotoxicity [23, 35, 41]. It has been reported that that CoQ10 supplements correlated with plasma CoQ10 level and CoQ10 in large doses was taken up all tissues including heart and brain mitochondria , suggesting that CoQ10 could also be taken up by retina and lead to a beneficial effect in ischemic retina injury. In support of this notion, a recent study demonstrated that oral supplementation of CoQ10 was neuroprotective against retinal damage induced by intravitreal injection of N-methyl-d-aspartate in mice in vivo . In the current study, we addressed the question of whether a CoQ10-supplemented diet inhibits oxidative stress-mediated mitochondrial dysfunction and RGC degeneration in ischemic retina.
We previously reported that acute IOP elevation triggers the upregulation of SOD2 protein expression and this increase could be restored by brimonidine (BMD)-mediated blockade of glutamate excitotoxicity-induced oxidative stress in ischemic rat retina . Consistent with these results, we have now found that the upregulation of SOD2 and HO-1 protein expression by acute IOP elevation was maximal early the neurodegeneration (12 h) of retinal ischemia. However, CoQ10 treatment decreases SOD2 and HO-1 protein expression in ischemic retina. Endogenous antioxidants such as mitochondrial SOD2 that localizes in the mitochondrial matrix and catalyzes the dismutation of superoxide radicals normally regulate ROS generated in mitochondria [44, 45]. It has been reported that SOD2 expression is increased by the stimulation of mitochondrial superoxide anion (O2 −)  and CoQ10 treatment could reduce the O2 − production . Growing evidence indicates that overexpression of the SOD2 gene inhibits retinal damage by reducing oxidative stress and nitrosative stress , as well as protecting retinal vascular cells and capillary degeneration against apoptotic cell death in mouse models of ischemic injury . Moreover, the upregulation of SOD2 is accompanied by a higher resistance to oxidative stress as well as SOD2 activity directly stabilizing mitochondrial transmembrane potential and calcium buffering ability [50, 51]. Our results, therefore, raise the possibility that increasing SOD2 or HO-1 expression in retinal ischemic injury may contribute to compensatory endogenous antioxidant mechanisms that increase resistance or stabilization of mitochondria against acute IOP elevation-induced oxidative stress. Taken together, it is noteworthy that these results suggest that CoQ10 could be an important antioxidant for ameliorating oxidative stress-mediated neurodegeneration in ischemic retina. Studying the benefits of CoQ10-mediated blockade of oxidative stress or enhancement of antioxidant enzymes may be a novel strategy for protecting retinal neurons against ischemic injury.
In the current study, we observed that CoQ10 treatment significantly promoted RGC survival as well as blocked activation of astroglial and microglial cells in ischemic retina. Astroglial or microglial activation coincides with RGC degeneration in the hypertensive retina of human, rat or mouse [3, 5, 37, 38, 39]. Thus, it is possible that CoQ10-mediated blockade of oxidative stress may indirectly reduce astroglial or microglial activation in the retina against elevated IOP-induced ischemic damage as a result of increased RGC survival. Regardless, it cannot be excluded that CoQ10 may prevent glial activation by blocking oxidative stress in astroglial or microglial cells in ischemic retina. CoQ10 is also neuroprotective in retinal glial cells against oxidative stress, since oxidative stress has remarkably linked to glial cell activation or reaction in the retina or optic nerve still needs to be ascertained [5, 52, 53, 54, 55, 56]. In addition, interestingly, it has been reported that IOP induced the upregulation of GFAP and major histochompatibility complex class II molecule, as well as of microglial activity in the controlateral control retinas in experimental rodent models of glaucoma induced by laser treatment [57, 58]. Although there was no evidence of glial activation in the contralateral non-ischemic control retina in the current study, future studies will need to clarify to use contralateral retina as an internal control in our ischemic model of mice.
Consistent with our result that CoQ10 promoted RGC survival in ischemic retina, we found that CoQ10 significantly decreased Bax, but increased pBad protein expression in ischemic retina. Bax is a pro-apoptotic member of the Bcl-2 family that is essential in many apoptotic pathways [59, 60] as well as directly interacts with the component forming the mitochondrial permeability transition pore (MPTP) that allows proteins to escape from the mitochondria into the cytosol to initiate apoptosis [61, 62, 63]. Bax is counteracted by Bcl-xL that forms heterodimers with dephosphorylation of Bad, which inactivates Bcl-xL; and pBad eliminates this dimerization, which activates Bcl-xL [64, 65]. Our collective results suggest that CoQ10 promotes RGC survival against the mitochondria-related apoptotic pathway in ischemic retinal injury by decreasing Bax, but by increasing pBad protein expression. These results reflect the possibility that increased pBad expression may represent an endogenous repair mechanism against apoptotic pathway and that CoQ10 may contribute to the blockade of Bax-mediated increase of MPT or the promotion of mitochondrial homeostasis in ischemic injury. The MPTP opening leads to loss of mitochondrial membrane potential, mitochondrial swelling, rupture of the outer mitochondrial membrane and release of cytochrome c. Importantly, MPTP opening by calcium overload and oxidative stress leads to necrosis rather than apoptosis [66, 67]. Recently, MPTP-mediated neuronal cell death has been implicated as an important pathophysiological mechanism for mitochondrial dysfunction in ischemic injury [24, 25]. Taken together, out findings suggest that CoQ10 may promote RGC survival by inhibiting not only apoptosis but also necrosis in ischemic retinal injury.
Ischemic injury triggers mitochondrial dysfunction including ROS induction as well as mtDNA damage, Tfam alteration or OXPHOS impairment in the central nervous system [5, 19, 68]. Recently, we have reported that acute IOP elevation significantly increased Tfam/OXPHOS complex protein expression and that blockade of glutamate excitotoxicity-induced oxidative stress by BMD treatment preserved Tfam/OXPHOS complex protein expression in ischemic retina , suggesting that the preservation of Tfam/OXPHOS complex may provide therapeutic potential for protecting RGCs against mitochondrial dysfunction induced by glutamate excitotoxicity and/or oxidative stress in ischemic retina . In the current study, we observed that retinal ischemic injury triggers significant increase of Tfam protein expression in the early neurodegenerative events (6–12 h) and CoQ10 decreases Tfam protein expression in ischemic retina at 12 h. Emerging evidence suggests that the Tfam and OXPHOS complex IV are rapidly increased in the early neurodegenerative events of neonatal hypoxic-ischemic brain injury, suggesting that Tfam may contribute to endogenous repair mechanism of injured brain neurons . Further, recent studies reported that overexpression of Tfam protects mitochondria against β–amyloid-induced oxidative damage in human SH-SY5Y neuroblastoma cells and ameliorates delayed neuronal cell death in the hippocampus following transient forebrain ischemia in mice [16, 17]. In contrast, in mice lacking Tfam there is impaired mtDNA transcription and mtDNA loss is triggered; this leads to mitochondrial bioenergetic dysfunction-mediated embryonic lethality .
Based on these results, we suggest that CoQ10-mediated preservation of Tfam expression may provide a potential mechanism for protecting RGCs against oxidative stress-induced mitochondrial dysfunction in ischemic retina. Future studies will examine the precise molecular mechanism underlying CoQ10-mediated Tfam preservation in ischemic retina. Although mtDNA is particularly susceptible to oxidative stress , it is unknown whether oxidative stress can directly trigger mtDNA alteration in ischemic retina. Interestingly, we found that there was no statistical difference in mtDNA content among control diet- and CoQ10 diet-treated groups. Because it has been reported that Tfam regulates mtDNA copy numbers in mammals and the levels of Tfam correlate with the levels of mtDNA [15, 70], our findings that did not show a correlation between Tfam protein expression and mtDNA content raise the possibility that increasing Tfam protein expression may prevent alteration of mtDNA content against oxidative stress in ischemic retina. Regardless, it would be useful to investigate mtDNA alteration on ischemic retina using measurements for 8-hydroxy-2-deoxyguanosine and mitochondrial membrane potential, and future studies need to address this more detail.
In conclusion, these results provide direct evidence that CoQ10 promotes RGC survival in ischemic mouse retina by inhibiting oxidative stress and by blocking the Bax/Bad-mediated mitochondrial apoptotic pathway. Moreover, CoQ10 also preserves Tfam protein expression in ischemic mouse retina. Based on these observations, we suggest that CoQ10 may provide a promising therapeutic potential for ameliorating oxidative stress-mediated mitochondrial dysfunction in ischemic retinal injury.
This work was supported, in part, by the National Institute Health Grants EY018658 (WKJ), NCRR P41 RR004050 and P41GM103412-24 (MHE) and P30EY022589 (Vision Research Core Grant), and a fund of Biomedical Research Institute of Chonbuk National University Hospital (DL) and an unrestricted grant from Research to Prevent Blindness (New York, NY, USA).
Conflict of interest
The authors declare that they have no conflict of interest.
- 29.Galindo-Romero C, Valiente-Soriano FJ, Jimenez-Lopez M, Valiente-Soriano FJ, Salinas-Navarro M, Nadal-Nicolas F et al (2013) Effect of brain-derived neurotrophic factor on mouse axotomized retinal ganglion cells and phagocytic microglia. Invest Ophthalmol Vis Sci 54:974–985PubMedCrossRefGoogle Scholar
- 30.Nadal-Nicolas FM, Jimenez-Lopez M, Sobrado-Calvo P, Nieto-Lopex L, Canovas-Martinez I, Salinas-Navarro M et al (2009) Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas. Invest Ophthalmol Vis Sci 50:3860–3868PubMedCrossRefGoogle Scholar
- 35.Lulli M, Witort E, Papucci L, Torre E, Schipani C, Bergamini C et al (2012) Coenzyme Q10 instilled as eye drops on the cornea reaches the retina and protects retinal layers from apoptosis in a mouse model of kainate-induced retinal damage. Invest Ophthalmol Vis Sci 53:8295–8302PubMedCrossRefGoogle Scholar
- 57.Ramirez AI, Salazar JJ, de Hoz R, Rojas B, Gallego BI, Sallinas-Navarro M et al (2010) Quantification of the effect of different levels of IOP in the astroglia of the rat retina ipsilateral and contralateral to experimental glaucoma. Invest Ophthalmol Vis Sci 51:5690–5696PubMedCrossRefGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.