bims-mideyd 2022-10-16 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022–10–16
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Cordyceps militaris Carotenoids Protect Human Retinal Endothelial Cells against the Oxidative Injury and Apoptosis Resulting from H2O2.
Targeting Phospholipase D Pharmacologically Prevents Phagocytic Function Loss of Retinal Pigment Epithelium Cells Exposed to High Glucose Levels.
Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.
Matrine promotes mitochondrial biosynthesis and reduces oxidative stress in experimental optic neuritis.
Potential therapeutic targets for age-related macular degeneration: The nuclear option.
Intrinsically photosensitive retinal ganglion cells in glaucoma.

Evid Based Complement Alternat Med. 2022 ;2022 1259093

Cordyceps militaris Carotenoids Protect Human Retinal Endothelial Cells against the Oxidative Injury and Apoptosis Resulting from H2O2.

Lin Lan, Shengyu Wang, Shuhua Duan, Xiangyu Zhou, Yufeng Li.

Vision loss is primarily caused by age-related macular degeneration (AMD) due to oxidative retinal pigment epithelial (RPE) cell injury. Carotenoid utilization is deemed a possible strategy for treating AMD. Cordyceps militaris has advantages like immunomodulatory, anti-inflammatory, and antioxidative characteristics. This paper assessed the possible protective influence of carotenoids obtained by isolating and purifying the Cordyceps militaris (CMCT) into human RPE cells (ARPE-19) damaged by hydrogen peroxide (H2O2). The findings demonstrated that CMCT safeguarded the ARPE-19 cells against the damage and apoptosis caused by H2O2 and oxidative stress via Bcl-2 protein upregulation, as well as the expression of Bax and cleaved caspase-3 protein. In addition, CMCT treatment increased cell survival and restricted the generation of H2O2-induced reactive oxygen species (ROS) and the protein expression of NADPH oxidase-1 (NOX1). Additionally, the CMCT treatment of H2O2-induced ARPE-19 cells ameliorated high malondialdehyde (MDA) levels in oxidative stress-induced cells. The catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) returned to standard levels, which were governed by the higher expression of nuclear Nrf2 protein in the ARPE-19 cells. Moreover, this study showed that CMCT safeguarded the ARPE-19 cells against the damage caused by oxidative stress via its antioxidant activity and antiapoptotic functionality, suggesting the potential therapeutic role of CMCT in AMD prevention and mitigation.

DOI: https://doi.org/10.1155/2022/1259093
Int J Mol Sci. 2022 Oct 05. pii: 11823. [Epub ahead of print]23(19):

Targeting Phospholipase D Pharmacologically Prevents Phagocytic Function Loss of Retinal Pigment Epithelium Cells Exposed to High Glucose Levels.

Vicente Bermúdez, Paula Estefanía Tenconi, María Sol Echevarría, Aram Asatrian, Jorgelina Muriel Calandria, Norma María Giusto, Nicolas Guillermo Bazan, Melina Valeria Mateos.

  We previously described the participation of canonical phospholipase D isoforms (PLD1 and PLD2) in the inflammatory response of retinal pigment epithelium (RPE) cells exposed to high glucose concentrations (HG). Here, we studied the role of the PLD pathway in RPE phagocytic function. For this purpose, ARPE-19 cells were exposed to HG (33 mM) or to normal glucose concentration (NG, 5.5 mM) and phagocytosis was measured using pHrodo™ green bioparticles® or photoreceptor outer segments (POS). HG exposure for 48 and 72 h reduced phagocytic function of ARPE-19 cells, and this loss of function was prevented when cells were treated with 5 μM of PLD1 (VU0359595 or PLD1i) or PLD2 (VU0285655-1 or PLD2i) selective inhibitors. Furthermore, PLD1i and PLD2i did not affect RPE phagocytosis under physiological conditions and prevented oxidative stress induced by HG. In addition, we demonstrated PLD1 and PLD2 expression in ABC cells, a novel human RPE cell line. Under physiological conditions, PLD1i and PLD2i did not affect ABC cell viability, and partial silencing of both PLDs did not affect ABC cell POS phagocytosis. In conclusion, PLD1i and PLD2i prevent the loss of phagocytic function of RPE cells exposed to HG without affecting RPE function or viability under non-inflammatory conditions.

Keywords:  inflammation; oxidative stress; phagocytosis; phospholipase D (PLD); retinal pigment epithelium (RPE)

DOI:  https://doi.org/10.3390/ijms231911823
Nat Commun. 2022 Oct 13. 13(1): 6045

Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

Haitao Liu, Nadezda A Stepicheva, Sayan Ghosh, Peng Shang, Olivia Chowdhury, Rachel A Daley, Meysam Yazdankhah, Urvi Gupta, Stacey L Hose, Mallika Valapala, Christopher Scott Fitting, Anastasia Strizhakova, Yang Shan, Derrick Feenstra, José-Alain Sahel, Ashwath Jayagopal, James T Handa, J Samuel Zigler, Patrice E Fort, Akrit Sodhi, Debasish Sinha.

The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease. We found that Akt1 and Akt2 activities were reciprocally regulated in the RPE of DR donor tissue and diabetic mice. Akt2 cKO attenuated diabetes-induced retinal abnormalities through a compensatory upregulation of phospho-Akt1 leading to an inhibition of vascular injury, inflammatory cytokine release, and infiltration of immune cells mediated by the GSK3β/NF-κB signaling pathway; overexpression of Akt2 has no effect. We propose that targeting Akt1 activity in the RPE may be a novel therapy for treating DR.

DOI: https://doi.org/10.1038/s41467-022-33773-0
Front Pharmacol. 2022 ;13 936632

Matrine promotes mitochondrial biosynthesis and reduces oxidative stress in experimental optic neuritis.

Yifan Song, Mengru Wang, Suyan Zhao, Yanjie Tian, Chun Zhang.

  Optic neuritis (ON), characterized by inflammation of the optic nerve and apoptosis of retinal ganglion cells (RGCs), is one of the leading causes of blindness in patients. Given that RGC, as an energy-intensive cell, is vulnerable to mitochondrial dysfunction, improving mitochondrial function and reducing oxidative stress could protect these cells. Matrine (MAT), an alkaloid derived from Sophora flavescens, has been shown to regulate immunity and protect neurons in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis and ON. However, the protective mechanism of MAT on RGCs is largely unknown. In this study, we show that MAT treatment significantly reduced the degree of inflammatory infiltration and demyelination of the optic nerve and increased the survival rate of RGCs. The expression of Sirtuin 1 (SIRT1), a member of an evolutionarily conserved gene family (sirtuins), was upregulated, as well as its downstream molecules Nrf2 and PGC-1α. The percentage of TOMM20-positive cells was also increased remarkably in RGCs after MAT treatment. Thus, our results indicate that MAT protects RGCs from apoptosis, at least in part, by activating SIRT1 to regulate PGC-1α and Nrf2, which, together, promote mitochondrial biosynthesis and reduce the oxidative stress of RGCs.

Keywords:  Nrf2; PGC-1α; SIRT1; matrine; mitochondrial biosynthesis; optic neuritis; oxidative stress

DOI:  https://doi.org/10.3389/fphar.2022.936632
Prog Retin Eye Res. 2022 Oct 08. pii: S1350-9462(22)00090-8. [Epub ahead of print] 101130

Potential therapeutic targets for age-related macular degeneration: The nuclear option.

Mayur Choudhary, Goldis Malek.

  The functions and activities of nuclear receptors, the largest family of transcription factors in the human genome, have classically focused on their ability to act as steroid and hormone sensors in endocrine organs. However, they are responsible for a diverse array of physiological functions, including cellular homeostasis and metabolism, during development and aging. Though the eye is not a traditional endocrine organ, recent studies have revealed high expression levels of nuclear receptors in cells throughout the posterior pole. These findings have precipitated an interest in investigating the role of these transcription factors in the eye as a function of age and ocular disease, in particular age-related macular degeneration (AMD). As the leading cause of vision impairment in the elderly, identifying signaling pathways that may be targeted for AMD therapy is of great importance, given the lack of therapeutic options for over 85% of patients with this disease. Herein we review this relatively new field and recent findings supporting the hypothesis that the eye is a secondary endocrine organ, in which nuclear receptors serve as the bedrock for biological processes in cells vulnerable in AMD, including retinal pigment epithelial and choroidal endothelial cells, and discuss the therapeutic potential of targeting these receptors for AMD.

Keywords:  Age-related macular degeneration; Aging; Choroidal endothelial cells; Nuclear receptors; Retinal pigment epithelium; Therapy

DOI:  https://doi.org/10.1016/j.preteyeres.2022.101130
Front Cell Neurosci. 2022 ;16 992747

Intrinsically photosensitive retinal ganglion cells in glaucoma.

Jingyi Gao, Ignacio Provencio, Xiaorong Liu.

  Glaucoma is a group of eye diseases afflicting more than 70 million people worldwide. It is characterized by damage to retinal ganglion cells (RGCs) that ultimately leads to the death of the cells and vision loss. The diversity of RGC types has been appreciated for decades, and studies, including ours, have shown that RGCs degenerate and die in a type-specific manner in rodent models of glaucoma. The type-specific loss of RGCs results in differential damage to visual and non-visual functions. One type of RGC, the intrinsically photosensitive retinal ganglion cell (ipRGC), expressing the photopigment melanopsin, serves a broad array of non-visual responses to light. Since its discovery, six subtypes of ipRGC have been described, each contributing to various image-forming and non-image-forming functions such as circadian photoentrainment, the pupillary light reflex, the photic control of mood and sleep, and visual contrast sensitivity. We recently demonstrated a link between type-specific ipRGC survival and behavioral deficits in a mouse model of chronic ocular hypertension. This review focuses on the type-specific ipRGC degeneration and associated behavioral changes in animal models and glaucoma patients. A better understanding of how glaucomatous insult impacts the ipRGC-based circuits will have broad impacts on improving the treatment of glaucoma-associated non-visual disorders.

Keywords:  glaucoma; ipRGC; ipRGC types; non-visual disorders; type-specific degeneration; vision loss

DOI:  https://doi.org/10.3389/fncel.2022.992747