bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2023–05–14
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington
  1. Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment.
  2. Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.
  3. Spatiotemporal Coordination of RPE Cell Quality by Extracellular Vesicle miR-494-3p Via Competitive Interplays With SIRT3 or PTEN.
  4. The roles of autophagy and mitophagy in corneal pathology: current knowledge and future perspectives.
  5. GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract.
  6. Tunneling nanotubes-based intercellular mitochondrial trafficking as a novel therapeutic target in dry eye.
  7. siRNA Mediated Downregulation of RhoA Expression Reduces Oxidative Induced Apoptosis in Retinal Ganglion Cells.
  1. Front Immunol. 2023 ;14 1138519
    Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment.
    R Scott Duncan, Andrew Keightley, Adam A Lopez, Conner W Hall, Peter Koulen.
      Age related macular degeneration (AMD) is the most common cause of blindness in the elderly. Oxidative stress contributes to retinal pigment epithelium (RPE) dysfunction and cell death thereby leading to AMD. Using improved RPE cell model systems, such as human telomerase transcriptase-overexpressing (hTERT) RPE cells (hTERT-RPE), pathophysiological changes in RPE during oxidative stress can be better understood. Using this model system, we identified changes in the expression of proteins involved in the cellular antioxidant responses after induction of oxidative stress. Some antioxidants such as vitamin E (tocopherols and tocotrienols) are powerful antioxidants that can reduce oxidative damage in cells. Alpha-tocopherol (α-Toc or αT) and gamma-tocopherol (γ-Toc or γT) are well-studied tocopherols, but signaling mechanisms underlying their respective cytoprotective properties may be distinct. Here, we determined what effect oxidative stress, induced by extracellularly applied tBHP in the presence and absence of αT and/or γT, has on the expression of antioxidant proteins and related signaling networks. Using proteomics approaches, we identified differential protein expression in cellular antioxidant response pathways during oxidative stress and after tocopherol treatment. We identified three groups of proteins based on biochemical function: glutathione metabolism/transfer, peroxidases and redox-sensitive proteins involved in cytoprotective signaling. We found that oxidative stress and tocopherol treatment resulted in unique changes in these three groups of antioxidant proteins indicate that αT and γT independently and by themselves can induce the expression of antioxidant proteins in RPE cells. These results provide novel rationales for potential therapeutic strategies to protect RPE cells from oxidative stress.
    Keywords:  gene ontology; oxidative stress; proteomics; retinal pigment epithelium (RPE) cells; tert-butyl hydroperoxide; tocopherol
    DOI:  https://doi.org/10.3389/fimmu.2023.1138519
  2. Life Sci Alliance. 2023 Aug;pii: e202301976. [Epub ahead of print]6(8):
    Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.
    Song Li, Tatjana C Jakobs.
      Glaucoma is a common neurodegenerative disorder characterized by retinal ganglion cell death, astrocyte reactivity in the optic nerve, and vision loss. Currently, lowering the intraocular pressure (IOP) is the first-line treatment, but adjuvant neuroprotective approaches would be welcome. Vitamin C possesses neuroprotective activities that are thought to be related to its properties as a co-factor of enzymes and its antioxidant effects. Here, we show that vitamin C promotes a neuroprotective phenotype and increases gene expression related to neurotropic factors, phagocytosis, and mitochondrial ATP production. This effect is dependent on the up-regulation of secreted phosphoprotein 1 (SPP1) in reactive astrocytes via the transcription factor E2F1. SPP1+ astrocytes in turn promote retinal ganglion cell survival in a mouse model of glaucoma. In addition, oral administration of vitamin C lowers the IOP in mice. This study identifies an additional neuroprotective pathway for vitamin C and suggests a potential therapeutic role of vitamin C in neurodegenerative diseases such as glaucoma.
    DOI:  https://doi.org/10.26508/lsa.202301976
  3. Invest Ophthalmol Vis Sci. 2023 05 01. 64(5): 9
    Spatiotemporal Coordination of RPE Cell Quality by Extracellular Vesicle miR-494-3p Via Competitive Interplays With SIRT3 or PTEN.
    Junji Hamuro, Tomoko Yamashita, Yohei Otsuki, Nao Hiramoto, Mayuka Adachi, Takafumi Miyatani, Hiroshi Tanaka, Morio Ueno, Shigeru Kinoshita, Chie Sotozono.
       Purpose: To reveal the molecular mechanism underlying degeneration in human retinal pigment epithelial (hRPE) cells with dysfunctional mitochondrial homeostasis.
    Methods: The expression of recently identified miR-494-3p in extracellular vesicles (EV) released from induced-pluripotential-stem-cell-derived human RPE (iPS-hRPE), during coculture with macrophages (Mps) was investigated in iPS-hRPE and ARPE cells differentiated in the presence of nicotinamide (Nic-ARPE). The expression of phosphatase and tensin homolog (PTEN), sirtuin3 (SIRT3), and mitochondrial marker proteins before and after the transfection of miR-494-3p inhibitor and mimic, and the changes in mitochondrial metabolism, membrane potential, and oxidative phosphorylation (OXPHOS) were monitored.
    Results: Compared with senescent dedifferentiated ARPE19 cells, iPS-hRPE and Nic-ARPE cells expressed elevated levels of mitochondrial marker proteins but a repressed cellular miR-494-3p level. The expression of target proteins of miR-494-3p, PTEN, and SIRT3 was upregulated along with the differentiation disposition of these RPE cells. The ratio of PTEN/SIRT3 in de-differentiated ARPE19 cells was surprisingly elevated by around 20 times compared with that in iPS-hRPE and Nic-ARPE cells. The novel molecular interplay of EV miR-494-3p either with mitochondria selective SIRT3 or organelle nonselective PTEN was found to participate in the degeneration of hRPE cells by inducing mitochondrial dysfunctions and repressed OXPHOS, mitochondrial membrane potential, and ATP and NAD+ production.
    Conclusions: Our results demonstrate a clear causal link between miR-494-3p and hRPE cell degeneration via the regulation of mitochondrial integrity. EV miR-494-3p may play a pivotal role in pathogenic spreading of degenerated hRPE cells from the local perifovea throughout the macula.
    DOI:  https://doi.org/10.1167/iovs.64.5.9
  4. Front Med (Lausanne). 2023 ;10 1064938
    The roles of autophagy and mitophagy in corneal pathology: current knowledge and future perspectives.
    Rajalakshmy Ayilam Ramachandran, Jose Marcos Sanches, Danielle M Robertson.
      The cornea is the clear dome that covers the front portion of the globe. The primary functions of the cornea are to promote the refraction of light and to protect the eye from invading pathogens, both of which are essential for the preservation of vision. Homeostasis of each cellular layer of the cornea requires the orchestration of multiple processes, including the ability to respond to stress. One mechanism whereby cells respond to stress is autophagy, or the process of "self-eating." Autophagy functions to clear damaged proteins and organelles. During nutrient deprivation, amino acids released from protein breakdown via autophagy are used as a fuel source. Mitophagy, a selective form of autophagy, functions to clear damaged mitochondria. Thus, autophagy and mitophagy are important intracellular degradative processes that sustain tissue homeostasis. Importantly, the inhibition or excessive activation of these processes result in deleterious effects on the cell. In the eye, impairment or inhibition of these mechanisms have been associated with corneal disease, degenerations, and dystrophies. This review summarizes the current body of knowledge on autophagy and mitophagy at all layers in the cornea in both non-infectious and infectious corneal disease, dystrophies, and degenerations. It further highlights the critical gaps in our understanding of mitochondrial dysfunction, with implications for novel therapeutics in clinical practice.
    Keywords:  autophagy; cornea; endothelium; epithelium; mitochondria; mitophagy; stroma
    DOI:  https://doi.org/10.3389/fmed.2023.1064938
  5. Free Radic Biol Med. 2023 May 06. pii: S0891-5849(23)00399-4. [Epub ahead of print]
    GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract.
    Dong-Yue Ma, Jin-Xia Liu, Lu-di Wang, Xin-Yu Zhi, Li Luo, Jiang-Yue Zhao, Yu Qin.
      Oxidative stress-induced lens epithelial cells (LECs) death plays a pivotal role in age-related cataract (ARC) with severe visual impairment, in which ferroptosis is gradually receiving numerous attention resulting from lipid peroxide accumulation and reactive oxygen species (ROS) overproduction. However, the essential pathogenic factors and the targeted medical strategies still remain skeptical and indistinct. In this work, by transmission electron microscopy (TEM) analysis, the major pathological courses in the LECs of ARC patients have been identified as ferroptosis, which was manifested with remarkable mitochondrial alterations, and similar results were found in aged mice (24-month-old). Furthermore, the primary pathological processes in the NaIO3-induced mice and HLE-B3 cell model have also been verified to be ferroptosis with an irreplaceable function of Nrf2, proved by the increased sensitivity to ferroptosis when Nrf2 was blocked in Nrf2-KO mice and si-Nrf2-treated HLE-B3 cells. Importantly, it has been found that an increased expression of GSK-3β was indicated in low-Nrf2-expressed tissues and cells. Subsequently, the contributions of abnormal GSK-3β expression to NaIO3-induced mice and HLE-B3 cell model were further evaluated, inhibition of GSK-3β utilizing SB216763 significantly alleviated LECs ferroptosis with less iron accumulation and ROS generation, as well as reversed expression alterations of ferroptosis markers, including GPX4, SLC7A11, SLC40A1, FTH1 and TfR1, in vitro and in vivo. Collectively, our findings conclude that targeting GSK-3β/Nrf2 balance might be a promising therapeutic strategy to mitigate LECs ferroptosis and thus probably delay the pathogenesis and development of ARC.
    Keywords:  Age-related cataract; Ferroptosis; GSK-3β; Nrf2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.04.022
  6. Exp Eye Res. 2023 May 09. pii: S0014-4835(23)00118-5. [Epub ahead of print] 109497
    Tunneling nanotubes-based intercellular mitochondrial trafficking as a novel therapeutic target in dry eye.
    Dan Jiang, Wei Xu, Fangli Peng, Yining Sun, Chengjie Pan, Jinjie Yu, Qinxiang Zheng, Wei Chen.
      Cell-to-cell mitochondria transfer via tunneling nanotubes (TNTs) has recently been revealed as a spontaneous way to protect damaged cells. Previously, we have reported mesenchymal stem cells (MSCs) can rescue retinal ganglion cell and corneal epithelium through intercellular mitochondrial trafficking. Mitochondrial damage and oxidative stress in corneal epithelial cells are vital in dry eye disease (DED). However, whether intercellular mitochondrial transfer is involved in the pathological and repair process of DED is currently unknown. Therefore, in this study, we designed a coculture system to evaluate the role of intercellular mitochondrial transfer between human corneal epithelial cells (CEC) in DED. In addition, we successfully discovered the ROCK inhibitor, Y-27632 as an intensifier to improve the efficiency of intercellular mitochondrial transport. As expected, the enhanced mitochondrial transfer promotes the regeneration of CECs. Moreover, through further exploration of mechanisms, it was demonstrated that F-actin-mediated cell morphological changes and cytoskeletal remodeling may be potential mechanisms for Y-27632 to induce mitochondrial metastasis. In conclusion, we established a new method for cell repair in DED that healthy CEC offered mitochondria to damaged CEC, providing a new insight into the cellular mechanism of corneal epithelium homeostatic regenerative therapeutics in DED.
    Keywords:  Corneal epithelial cells; Cytoskeleton; Dry eye disease; Mitochondrial transfer; Y-27632
    DOI:  https://doi.org/10.1016/j.exer.2023.109497
  7. Curr Mol Med. 2023 May 11.
    siRNA Mediated Downregulation of RhoA Expression Reduces Oxidative Induced Apoptosis in Retinal Ganglion Cells.
    Qian Liu, Changgeng Liu, Bo Lei.
       BACKGROUNDS: Glaucoma is the second leading cause of blindness. Apoptosis of retinal ganglion cells (RGCs) is an important mechanism of glaucomatous optic injury. Rho kinase expression is significantly increased in apoptotic RGCs. This study aimed to investigate the role of RhoA, a Rho GTPase, on the survival of RGCs and further to explore its potential therapeutic applications.
    METHODS: RGCs were treated with siRhoA for 24 hours in vitro. Knockdown of RhoA was confirmed with quantitative RT-PCR. Oxidative stress was induced by treating the RGCs with 200 μM of H2O2 for 1 hour, and apoptosis of RGCs was quantified with TUNEL assay in situ, and with flow cytometry. The mRNA expression levels of RhoA, Nogo receptor, caspase 3 and Bcl-2 were evaluated by quantitative RT-PCR, and the protein levels of RhoA, ROCK1, ROCK2, Nogo receptor, caspase 3 and Bcl-2 were evaluated by Western blot. We found siRhoA treatment efficiently downregulated the expression of RhoA in RGCs and protected against H2O2-induced injury in RGCs in vitro. Apoptosis of RGC cells under oxidative stress was quantified in situ using TUNEL assay and confirmed with flow cytometry (FCM).
    RESULTS: With the knockdown of RhoA, the expression of ROCK1, ROCK2, Nogo Receptor, Casepase-3 were decreased, while the expression of Bcl-2 was increased in both mRNA and protein level. Our data indicated that siRhoA prevented H2O2-induced apoptosis in RGC cells by modulating the RhoA/ROCK pathway.
    CONCLUSION: The results suggested that siRhoA may exert potentially effective neuroprotection for RGCs by reducing injury.
    Keywords:  Keywords: siRNA; RhoA? Retinal Ganglion Cells? Apoptosis?Oxidative?Glaucoma
    DOI:  https://doi.org/10.2174/1566524023666230511095628
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