bims-mideyd 2022-01-23 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022‒01‒23
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro.
Differential Mechanisms of Action and Efficacy of Vitamin E Components in Antioxidant Cytoprotection of Human Retinal Pigment Epithelium.
Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.
Fine Tuning of an Oxidative Stress Model with Sodium Iodate Revealed Protective Effect of NF-κB Inhibition and Sex-Specific Difference in Susceptibility of the Retinal Pigment Epithelium.
Ligustrazine protects against chronic hypertensive glaucoma in rats by inhibiting autophagy via the PI3K-Akt/mTOR pathway.
Influences of glaucoma on the structure and function of synapses in the visual system.
The H+ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling.

Biomedicines. 2022 Jan 12. pii: 159. [Epub ahead of print]10(1):

Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro.

Hao-Yu Tsai, Henkie Isahwan Ahmad Mulyadi Lai, Zhang-Yuan Chen, Tai-Chi Lin, Winnie Khor, Wen-Chuan Kuo, Jia-Pu Syu, Ping-Hsing Tsai, Yi-Ping Yang, Yueh Chien, Shih-Jen Chen, De-Kuang Hwang, Shih-Hwa Chiou, Shih-Jie Chou.

  Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina's autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.

Keywords:  DUSP6; ERK; NaIO3; autophagy; autophagy flux; retinal degeneration; retinal pigment epithelium

DOI:  https://doi.org/10.3390/biomedicines10010159
Front Pharmacol. 2021 ;12 798938

Differential Mechanisms of Action and Efficacy of Vitamin E Components in Antioxidant Cytoprotection of Human Retinal Pigment Epithelium.

R Scott Duncan, Daniel T Hurtado, Conner W Hall, Peter Koulen.

  The purpose of this study was to determine if different vitamin E components exhibit similar efficacy and mechanism of action in protecting Retinal pigment epithelium (RPE) cells from oxidative damage. We hypothesized that α-tocopherol (αT) is unique among vitamin E components in its cytoprotective mechanism of action against oxidative stress in RPE cells and that it requires protein synthesis for optimal antioxidant effect. We used cell viability assays, fluorescent chemical labeling of DNA and actin and immuno-labeling of the antioxidant proteins Nrf2 and Sod2 and of the tight junction protein, ZO-1, and confocal microscopy to determine the effects of αT and γT against oxidative stress in immortalized human RPE cells (hTERT-RPE). Using the four main vitamin E components, αT, γT, δ-tocopherol (δT) and α-tocotrienol (αTr), we ascertained that they exhibit similar, but not identical, antioxidant activity as αT when used at equimolar concentrations. In addition, we determined that the exposure time of RPE cells to α-tocopherol is critical for its ability to protect against oxidative damage. Lastly, we determined that αT, but not γT, partially requires the synthesis of new proteins within a 24-h period and prior to exposure to tBHP for optimal cytoprotection. We conclude that, unlike γT and δT, αT appears to be unique in its requirement for transport and/or signaling for it to be an effective antioxidant. As a result, more focus should be paid to which vitamin E components are used for antioxidant interventions.

Keywords:  age related macular degeneration (AMD); antioxidant; oxidative stress; retina; retinal pigment epithelium (RPE); tocopherol; vitamin E

DOI:  https://doi.org/10.3389/fphar.2021.798938
Nat Commun. 2022 Jan 18. 13(1): 374

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.

Jen-Zen Chuang, Nan Yang, Nobuyuki Nakajima, Wataru Otsu, Cheng Fu, Howard Hua Yang, Maxwell Ping Lee, Armaan Fazal Akbar, Tudor Constantin Badea, Ziqi Guo, Afnan Nuruzzaman, Kuo-Shun Hsu, Joshua L Dunaief, Ching-Hwa Sung.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

DOI: https://doi.org/10.1038/s41467-021-27935-9
Antioxidants (Basel). 2021 Dec 31. pii: 103. [Epub ahead of print]11(1):

Fine Tuning of an Oxidative Stress Model with Sodium Iodate Revealed Protective Effect of NF-κB Inhibition and Sex-Specific Difference in Susceptibility of the Retinal Pigment Epithelium.

Xue Yang, Usha Rai, Jin-Yong Chung, Noriko Esumi.

  Oxidative stress of the retinal pigment epithelium (RPE) is a major risk factor for age-related macular degeneration (AMD). As a dry AMD model via oxidative stress, sodium iodate (NaIO3), which is primarily toxic to the RPE, has often been used at a high dose to cause RPE death for studying photoreceptor degeneration. Thus, characterization of RPE damage by a low dose of NaIO3 is still limited. To quantify RPE damage caused by NaIO3 in mice, we recently developed a morphometric method using RPE flat-mounts. Here, we report that NaIO3 has a narrow range of dose-effect correlation at 11-18 mg/kg body weight in male C57BL/6J mice. We evaluated the usefulness of our quantification method in two experimental settings. First, we tested the effect of NF-κB inhibition on NaIO3-induced RPE damage in male C57BL/6J mice. IKKβ inhibitor BAY 651942 suppressed upregulation of NF-κB targets and protected the RPE from oxidative stress. Second, we tested sex-specific differences in NaIO3-induced RPE damage in C57BL/6J mice using a low dose near the threshold. NaIO3 caused more severe RPE damage in female mice than in male mice. These results demonstrate the usefulness of the quantification method and the importance of fine-tuning of the NaIO3 dose. The results also show the therapeutic potential of IKKβ inhibition for oxidative stress-related RPE diseases, and reveal previously-unrecognized sex-specific differences in RPE susceptibility to oxidative stress.

Keywords:  IKKbeta; NF-kappaB; anti-oxidant; catalase; oxidative stress; retinal pigment epithelium; sex differences; sodium iodate

DOI:  https://doi.org/10.3390/antiox11010103
Mol Vis. 2021 ;27 725-733

Ligustrazine protects against chronic hypertensive glaucoma in rats by inhibiting autophagy via the PI3K-Akt/mTOR pathway.

Hong-Yan Du, Rong Wang, Jian-Liang Li, Huang Luo, Xiao-Yan Xie, Ran Yan, Yue-Ling Jian, Jin-Ying Cai.

Purpose: Glaucoma is a leading cause of global irreversible blindness, and characterized by the progressive loss of retinal ganglion cells (RGCs). Ligustrazine (TMP) is a natural product that has shown beneficial effects on various diseases. This study aimed to determine whether ligustrazine produces a therapeutic effect on glaucoma and to investigate its underlying mechanisms.Methods: A rat chronic hypertensive glaucoma model was induced by episcleral vein cauterization (EVC). Adult Sprague-Dawley (SD) rats were intraperitoneally administered TMP at a dose of 80 mg/kg once a day, from two days before EVC to one month after EVC. To elucidate the role of the mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K), TMP-treated experimental rats were co-treated with the mTOR inhibitor rapamycin (5 mg/kg) or the PI3K inhibitor Ly294002 (10 mg/kg). The intraocular pressure (IOP) of the experimental and control rats was measured every six days. Retinal cells were examined by hematoxylin-eosin and terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling (TUNEL) staining, as well as transmission electron microscopy. Immunohistochemistry and western blot analysis were performed to measure proteins involved in apoptosis and autophagy.
Results: Ligustrazine protected retinal cells from death in experimental glaucoma rats, which was not due to the lowering of IOP, but could be attributable to direct suppression of retinal cell apoptosis. In glaucoma rats, autophagy was markedly activated in retina cells, as evidenced by increased numbers of autophagosomes and the expression of autophagy-related proteins (ATG5 and LC3-II/I). Notably, such alterations in glaucoma rats were almost completely reversed by ligustrazine. The suppressive effects of ligustrazine on apoptosis and autophagy of retina cells were markedly attenuated by the mTOR inhibitor rapamycin or the PI3K inhibitor Ly294002. Additionally, ligustrazine significantly increased the protein levels of phosphorylated PI3K (p-PI3K), protein kinase B (p-Akt), and mTOR (p-mTOR) in glaucoma rats, whereas such increases were attenuated by rapamycin or Ly294002.
Conclusions: These results demonstrate that ligustrazine is protective in experimental glaucoma by inhibiting autophagy via the activation of the PI3K-Akt/mTOR pathway, providing compelling evidence that ligustrazine is potentially therapeutic for patients with glaucoma.
Antioxid Redox Signal. 2022 Jan 19.

Influences of glaucoma on the structure and function of synapses in the visual system.

Matthew Van Hook.

SIGNIFICANCE: Glaucoma is an age-related neurodegenerative disorder of the visual system associated with sensitivity to intraocular pressure (IOP). It is the leading irreversible cause of vision loss worldwide and vision loss results from damage and dysfunction of the retinal output neurons known as retinal ganglion cells (RGCs). Recent Advances: Elevated IOP and optic nerve injury triggers pruning of RGC dendrites, altered morphology of excitatory inputs from presynaptic bipolar cells, and disrupted RGC synaptic function. Less is known about RGC outputs, although evidence to date indicates that glaucoma is associated with altered mitochondrial and synaptic structure and function in RGC-projection targets in the brain. These early functional changes likely contribute to vision loss and might be a window into early diagnosis and treatment.CRITICAL ISSUES: Glaucoma affects different RGC populations to varying extents and along distinct time courses. The influence of glaucoma on RGC synaptic function as well as the mechanisms underlying these effects remain to be determined. Since RGCs are an especially energetically-demanding population of neurons, altered intracellular axon transport of mitochondria and mitochondrial function might contribute to RGC synaptic dysfunction in the retina brain as well as RGC vulnerability in glaucoma.
FUTURE DIRECTIONS: The mechanisms underlying differential RGC vulnerability remain to be determined. Moreover, the timing and mechanisms of RGCs synaptic dysfunction and degeneration will provide valuable insight into the disease process in glaucoma. Future work will be able to capitalize on these findings to better design diagnostic and therapeutic approaches to detect disease and prevent vision loss.

DOI: https://doi.org/10.1089/ars.2021.0253
Cells. 2022 Jan 07. pii: 197. [Epub ahead of print]11(2):

The H+ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling.

Joseph A Bonanno, Raji Shyam, Moonjung Choi, Diego G Ogando.

  Solute-linked cotransporter, SLC4A11, a member of the bicarbonate transporter family, is an electrogenic H+ transporter activated by NH3 and alkaline pH. Although SLC4A11 does not transport bicarbonate, it shares many properties with other members of the SLC4 family. SLC4A11 mutations can lead to corneal endothelial dystrophy and hearing deficits that are recapitulated in SLC4A11 knock-out mice. SLC4A11, at the inner mitochondrial membrane, facilitates glutamine catabolism and suppresses the production of mitochondrial superoxide by providing ammonia-sensitive H+ uncoupling that reduces glutamine-driven mitochondrial membrane potential hyperpolarization. Mitochondrial oxidative stress in SLC4A11 KO also triggers dysfunctional autophagy and lysosomes, as well as ER stress. SLC4A11 expression is induced by oxidative stress through the transcription factor NRF2, the master regulator of antioxidant genes. Outside of the corneal endothelium, SLC4A11's function has been demonstrated in cochlear fibrocytes, salivary glands, and kidneys, but is largely unexplored overall. Increased SLC4A11 expression is a component of some "glutamine-addicted" cancers, and is possibly linked to cells and tissues that rely on glutamine catabolism.

Keywords:  MCT4; ammonia; corneal endothelial dystrophy; glutamine; lactate

DOI:  https://doi.org/10.3390/cells11020197