bims-mideyd 2022-05-29 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022–05–29
nine papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma.
Impacts of Bacteriostatic and Bactericidal Antibiotics on the Mitochondria of the Age-Related Macular Degeneration Cybrid Cell Lines.
DNA and RNA oxidative damage in the retina is associated with ganglion cell mitochondria.
Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells.
Shabyar Ameliorates High Glucose Induced Retinal Pigment Epithelium Injury Through Suppressing Aldose Reductase and AMPK/mTOR/ULK1 Autophagy Pathway.
High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells.
cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.
Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration.
Oxidative-Induced Angiogenesis Is Modulated by Small Extracellular Vesicle miR-302a-3p Cargo in Retinal Pigment Epithelium Cells.

Antioxidants (Basel). 2022 Apr 29. pii: 886. [Epub ahead of print]11(5):

The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma.

Daire John Hurley, Caoimhe Normile, Mustapha Irnaten, Colm O'Brien.

  Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment.

Keywords:  endoplasmic reticulum stress; glaucoma; novel therapies; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox11050886
Biomolecules. 2022 May 07. pii: 675. [Epub ahead of print]12(5):

Impacts of Bacteriostatic and Bactericidal Antibiotics on the Mitochondria of the Age-Related Macular Degeneration Cybrid Cell Lines.

Nasim Salimiaghdam, Lata Singh, Mithalesh K Singh, Marilyn Chwa, Shari R Atilano, Zahra Mohtashami, Anthony B Nesburn, Baruch D Kuppermann, Stephanie Y Lu, M Cristina Kenney.

  We assessed the potential negative effects of bacteriostatic and bactericidal antibiotics on the AMD cybrid cell lines (K, U and J haplogroups). AMD cybrid cells were created and cultured in 96-well plates and treated with tetracycline (TETRA) and ciprofloxacin (CPFX) for 24 h. Reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔψM), cellular metabolism and ratio of apoptotic cells were measured using H2DCFDA, JC1, MTT and flow cytometry assays, respectively. Expression of genes of antioxidant enzymes, and pro-inflammatory and pro-apoptotic pathways were evaluated by quantitative real-time PCR (qRT-PCR). Higher ROS levels were found in U haplogroup cybrids when treated with CPFX 60 µg/mL concentrations, lower ΔψM of all haplogroups by CPFX 120 µg/mL, diminished cellular metabolism in all cybrids with CPFX 120 µg/mL, and higher ratio of dead cells in K and J cybrids. CPFX 120 µg/mL induced overexpression of IL-33, CASP-3 and CASP-9 in all cybrids, upregulation of TGF-β1 and SOD2 in U and J cybrids, respectively, along with decreased expression of IL-6 in J cybrids. TETRA 120 µg/mL induced decreased ROS levels in U and J cybrids, increased cellular metabolism of treated U cybrids, higher ratio of dead cells in K and J cybrids and declined ΔψM via all TETRA concentrations in all haplogroups. TETRA 120 µg/mL caused upregulation of IL-6 and CASP-3 genes in all cybrids, higher CASP-7 gene expression in K and U cybrids and downregulation of the SOD3 gene in K and U cybrids. Clinically relevant dosages of ciprofloxacin and tetracycline have potential adverse impacts on AMD cybrids possessing K, J and U mtDNA haplogroups in vitro.

Keywords:  AMD cybrids; antibiotics; bactericidal; bacteriostatic; mtDNA haplogroups

DOI:  https://doi.org/10.3390/biom12050675
Sci Rep. 2022 May 24. 12(1): 8705

DNA and RNA oxidative damage in the retina is associated with ganglion cell mitochondria.

Lei Gu, Jacky M Kwong, Joseph Caprioli, Natik Piri.

This study examines retinas from a rat glaucoma model for oxidized nucleosides 8OHdG and 8OHG, biomarkers for oxidative damage of DNA and RNA, respectively. Immunohistochemical data indicate a predominant localization of 8OHdG/8OHG in retinal ganglion cells (RGCs). The levels for these oxidized DNA/RNA products were 3.2 and 2.8 fold higher at 1 and 2 weeks after intraocular pressure elevation compared to control retinas, respectively. 8OHdG/8OHG were almost exclusively associated with mitochondrial DNA/RNA: ~ 65% of 8OHdG/8OHG were associated with RNA isolated from mitochondrial fraction and ~ 35% with DNA. Furthermore, we analyzed retinas of the rd10 mouse, a model for retinitis pigmentosa, with severe degeneration of photoreceptors to determine whether high levels of 8OHdG/8OHG staining intensity in RGCs of control animals is related to the high level of mitochondrial oxidative phosphorylation necessary to support light-evoked RGC activity. No significant difference in 8OHdG/8OHG staining intensity between control and rd10 mouse retinas was observed. The results of this study suggest that high levels of 8OHdG/8OHG in RGCs of wild-type animals may lead to cell damage and progressive loss of RGCs observed during normal aging, whereas ocular hypertension-induced increase in the level of oxidatively damaged mitochondrial DNA/RNA could contribute to glaucomatous neurodegeneration.

DOI: https://doi.org/10.1038/s41598-022-12770-9
Front Cell Dev Biol. 2022 ;10 900777

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells.

Xuejing Yan, Shen Wu, Qian Liu, Ying Cheng, Jingxue Zhang, Ningli Wang.

  Trabecular meshwork dysfunction is the main cause of primary open angle glaucoma (POAG) associated with elevated intraocular pressure (IOP). Mutant myocilin causes glaucoma mainly via elevating IOP. Previously we have found that accumulated Asn 450 Tyr (N450Y) mutant myocilin impairs human trabecular meshwork (TM) cells by inducing chronic endoplasmic reticulum (ER) stress response in vitro. However, it is unclear how ER stress leads to TM damage and whether N450Y myocilin mutation is associated with POAG in vivo. Here we found that N450Y mutant myocilin induces autophagy, which worsens cell viability, whereas inhibition of autophagy increases viability and decreases cell death in human TM cells. Furthermore, we construct a transgenic mouse model of N450Y myocilin mutation (Tg-MYOCN450Y) and Tg-MYOCN450Y mice exhibiting glaucoma phenotypes: IOP elevation, retinal ganglion cell loss and visual impairment. Consistent with our published in vitro studies, mutant myocilin fails to secrete into aqueous humor, causes ER stress and actives autophagy in Tg-MYOCN450Y mice, and aqueous humor dynamics are altered in Tg-MYOCN450Y mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG.

Keywords:  ER stress; POAG; autophagy; myocilin; trabecular meshwork

DOI:  https://doi.org/10.3389/fcell.2022.900777
Front Pharmacol. 2022 ;13 852945

Shabyar Ameliorates High Glucose Induced Retinal Pigment Epithelium Injury Through Suppressing Aldose Reductase and AMPK/mTOR/ULK1 Autophagy Pathway.

Xiao Yan Liu, Jun Peng, Fei He, Xirali Tursun, Shu Ping Li, Xue Lei Xin, Haji Akber Aisa.

  Shabyar (SBA) is a traditional medicine formula for relieving vision loss caused by factors including diabetic retinopathy (DR) in clinics. However, the mechanism of it on retina protective effect still unclear. The present study aimed to investigate whether its protective effect was related to aldose reductase (AR) inhibition and retinal pigment epithelial cell injury mediated by autophagy or not. Human retinal pigment epithelial cells (ARPE-19) induced by high glucose was used as a model in vitro, with Epalrestat (EPL, AR inhibitor) and Difrarel (DFR, DR therapeutic drug) as positive controls. Western blotting and Polyol pathway products assay showed that SBA reduced the expression of AR protein and the content of ROS, and sorbitol, increased the level of Na+-K+-ATPase and alleviated cell edema. Western blotting and DCFH-DA probe assay showed that SBA decreased pAMPK/AMPK and pULK1/ULK1 which associated with autophagy initiation, down-regulated Beclin-1, Atg3, Atg5, Atg7, LC3 II and Bax/Bcl2 ratio, and up-regulated pmTOR/mTOR, SQSTM1/p62 and mitochondrial membrane potential (MMP), reduces intracellular autophagosomes. Real-Time PCR assay showed that SBA had no significant effect on mRNA expression of AR and mTOR. These data demonstrated that SBA treatment inhibits the autophagy of ARPE-19 through the AMPK/mTOR/ULK1 signaling pathway, and reduced early-stage apoptosis occurred by high glucose. These findings reveal the protective role and mechanism of SBA on retinal pigment epithelium, and provide experimental basis for the clinical application of SBA in the treatment of DR.

Keywords:  aldose reductase; autophagy; retinal pigment epithelium; shabyar; traditional medicine formula

DOI:  https://doi.org/10.3389/fphar.2022.852945
Endocrine. 2022 May 25.

High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells.

A Mecchia, C Palumbo, A De Luca, D Sbardella, A Boccaccini, L Rossi, M Parravano, M Varano, A M Caccuri.

   PURPOSE: We investigated the autophagic response of rat Müller rMC-1 cells during a short-term high glucose challenge.
METHODS: rMC-1 cells were maintained in 5 mM glucose (LG) or exposed to 25 mM glucose (HG). Western blot analysis was used to evaluate the expression levels of markers of autophagy (LC3-II, p62) and glial activation (AQP4), as well as the activation of TRAF2/JNK, ERK and AKT pathways. Autophagic flux assessment was performed using the autophagy inhibitor chloroquine. ROS levels were measured by flow cytometry using dichlorofluorescein diacetate. ERK involvement in autophagy induction was addressed using the ERK inhibitor FR180204. The effect of autophagy inhibition on cell viability was evaluated by SRB assay.
RESULTS: Activation of autophagy was observed in the first 2-6 h of HG exposure. This early autophagic response was transient, not accompanied by an increase in AQP4 or in the phospho-activation of JNK, a key mediator of cellular response to oxidative stress, and required ERK activity. Cells exposed to HG had a lower viability upon autophagy inhibition by chloroquine, as compared to those maintained in LG.
CONCLUSION: A short-term HG challenge triggers in rMC-1 cells a process improving the ability to cope with stressful conditions, which involves ERK and an early and transient autophagy activation.

Keywords:  Autophagy; Diabetes; ERK; Glial cells; Retina

DOI:  https://doi.org/10.1007/s12020-022-03079-8
Cell Mol Neurobiol. 2022 May 27.

cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.

Jorgelina M Calandria, Khanh V Do, Sayantani Kala-Bhattacharjee, Andre Obenaus, Ludmila Belayev, Nicolas G Bazan.

  Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke.

Keywords:  Human RPE cells; Inflammatory cytokines; Ischemia–reperfusion; Neuroprotectin D1; Neuroprotection; Non-conventional cytokine; Retinal pigment epithelial cells; Stroke; Uncompensated oxidative stress; Wnt5a promoter

DOI:  https://doi.org/10.1007/s10571-022-01231-6
Front Neurosci. 2022 ;16 890021

Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration.

Genea Edwards, Caroline G Olson, Carlyn P Euritt, Peter Koulen.

  The eye is particularly susceptible to oxidative stress and disruption of the delicate balance between oxygen-derived free radicals and antioxidants leading to many degenerative diseases. Attention has been called to all isoforms of vitamin E, with α-tocopherol being the most common form. Though similar in structure, each is diverse in antioxidant activity. Preclinical reports highlight vitamin E's influence on cell physiology and survival through several signaling pathways by activating kinases and transcription factors relevant for uptake, transport, metabolism, and cellular action to promote neuroprotective effects. In the clinical setting, population-based studies on vitamin E supplementation have been inconsistent at times and follow-up studies are needed. Nonetheless, vitamin E's health benefits outweigh the controversies. The goal of this review is to recognize the importance of vitamin E's role in guarding against gradual central vision loss observed in age-related macular degeneration (AMD). The therapeutic role and molecular mechanisms of vitamin E's function in the retina, clinical implications, and possible toxicity are collectively described in the present review.

Keywords:  age-related macular degeneration (AMD); antioxidant; retina; tocopherol; tocotrienol; vitamin E

DOI:  https://doi.org/10.3389/fnins.2022.890021
Antioxidants (Basel). 2022 Apr 22. pii: 818. [Epub ahead of print]11(5):

Oxidative-Induced Angiogenesis Is Modulated by Small Extracellular Vesicle miR-302a-3p Cargo in Retinal Pigment Epithelium Cells.

Maria Oltra, Miriam Martínez-Santos, María Ybarra, Hugo Rowland, María Muriach, Javier Romero, Javier Sancho-Pelluz, Jorge M Barcia.

  Extracellular vesicles are released from cells under diverse conditions. Widely studied in cancer, they are associated with different diseases playing major roles. Recent reports indicate that oxidative damage promotes the release of small extracellular vesicle (sEVs) from the retinal pigment epithelium (RPE), with an angiogenic outcome and changes in micro-RNA (miRNA) levels. The aim of this study was to determine the role of the miRNA miR-302a-3p, included within RPE-released sEVs, as an angiogenic regulator in cultures of endothelial cells (HUVEC). ARPE-19 cell cultures, treated with H2O2 to cause an oxidative insult, were transfected with a miR-302a-3p mimic. Later, sEVs from the medium were isolated and added into HUVEC or ARPE-19 cultures. sEVs from ARPE-19 cells under oxidative damage presented a decrease of miR-302a-3p levels and exhibited proangiogenic properties. In contrast, sEVs from miR-302a-3p-mimic transfected cells resulted in control angiogenic levels. The results herein indicate that miR-302a-3p contained in sEVs can modify VEGFA mRNA expression levels as part of its antiangiogenic features.

Keywords:  microRNAs; retinal pigment epithelial cells; small extracellular vesicles; vasculogenesis

DOI:  https://doi.org/10.3390/antiox11050818