bims-mideyd 2023-06-25 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2023–06–25
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.
Single-cell transcriptomics reveals maturation of transplanted stem cell-derived retinal pigment epithelial cells toward native state.
Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering.
Importance of DJ-1 in autophagy regulation and disease.
Astaxanthin inhibits oxidative stress and apoptosis in diabetic retinopathy.
Retinal pigment epithelium exhibits gene expression and phagocytic activity alterations when exposed to retinoblastoma chemotherapeutics.

Redox Biol. 2023 Jun 15. pii: S2213-2317(23)00187-8. [Epub ahead of print]64 102786

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.

Ponarulselvam Sekar, George Hsiao, Shu-Hao Hsu, Duen-Yi Huang, Wan-Wan Lin, Chi-Ming Chan.

  Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.

Keywords:  AMPK; Diabetic retinopathy; Glyoxalase 1; Metformin; Methylglyoxal; Mitochondria; Retinal pigment epithelial cells

DOI:  https://doi.org/10.1016/j.redox.2023.102786
Proc Natl Acad Sci U S A. 2023 06 27. 120(26): e2214842120

Single-cell transcriptomics reveals maturation of transplanted stem cell-derived retinal pigment epithelial cells toward native state.

Bhav Harshad Parikh, Paul Blakeley, Kakkad Regha, Zengping Liu, Binxia Yang, Mayuri Bhargava, Daniel Soo Lin Wong, Queenie Shu Woon Tan, Claudine See Wei Wong, Hao Fei Wang, Abdurrahmaan Al-Mubaarak, Chai Chou, Chui Ming Gemmy Cheung, Kah Leong Lim, Veluchamy Amutha Barathi, Walter Hunziker, Gopal Lingam, Tim Xiaoming Hu, Xinyi Su.

  Transplantation of stem cell-derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation, and fate specification of transplanted RPE cells. To address this, we transplanted stem cell-derived RPE into the subretinal space of immunocompetent rabbits for 1 mo and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory-inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation toward the native adult human RPE state in all transplanted RPE, regardless of stem cell resource. Gene regulatory network analysis suggests that tripartite transcription factors (FOS, JUND, and MAFF) may be specifically activated in posttransplanted RPE cells, to regulate canonical RPE signature gene expression crucial for supporting host photoreceptor function, and to regulate prosurvival genes required for transplanted RPE's adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD.

Keywords:  cell transplantation; pluripotent stem cell; retinal pigment epithelium; transcriptome

DOI:  https://doi.org/10.1073/pnas.2214842120
Mol Aspects Med. 2023 Jun 16. pii: S0098-2997(23)00033-X. [Epub ahead of print]92 101193

Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering.

James R Tribble, Flora Hui, Heberto Quintero, Sana El Hajji, Katharina Bell, Adriana Di Polo, Pete A Williams.

  Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons of the retina. Glaucoma is the most common cause of irreversible blindness and affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, and elevated intraocular pressure. Current strategies only target intraocular pressure management and do not directly target the neurodegenerative processes occurring at the level of the retinal ganglion cell. Despite strategies to manage intraocular pressure, as many as 40% of glaucoma patients progress to blindness in at least one eye during their lifetime. As such, neuroprotective strategies that target the retinal ganglion cell and these neurodegenerative processes directly are of great therapeutic need. This review will cover the recent advances from basic biology to on-going clinical trials for neuroprotection in glaucoma covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, and neuroinflammation. With an increased understanding of both the basic and clinical mechanisms of the disease, we are closer than ever to a neuroprotective strategy for glaucoma.

Keywords:  Apoptosis; Autophagy; Axon degeneration; Axon transport; Calcium signaling; Glaucoma; Insulin; Metabolism; Mitochondria; Neurodegeneration; Neuroinflammation; Neuroprotection; Optic nerve; Retinal ganglion cell; mTOR

DOI:  https://doi.org/10.1016/j.mam.2023.101193
Arch Biochem Biophys. 2023 Jun 17. pii: S0003-9861(23)00171-6. [Epub ahead of print] 109672

Importance of DJ-1 in autophagy regulation and disease.

Shiyi Liu, Sheng Xu, Song Liu, Heping Chen.

  Autophagy is a highly conserved biological process that has evolved across evolution. It can be activated by various external stimuli including oxidative stress, amino acid starvation, infection, and hypoxia. Autophagy is the primary mechanism for preserving cellular homeostasis and is implicated in the regulation of metabolism, cell differentiation, tolerance to starvation conditions, and resistance to aging. As a multifunctional protein, DJ-1 is commonly expressed in vivo and is associated with a variety of biological processes. Its most widely studied role is its function as an oxidative stress sensor that inhibits the production of excessive reactive oxygen species (ROS) in the mitochondria and subsequently the cellular damage caused by oxidative stress. In recent years, many studies have identified DJ-1 as another important factor regulating autophagy; it regulates autophagy in various ways, most commonly by regulating the oxidative stress response. In particular, DJ-1-regulated autophagy is involved in cancer progression and plays a key role in alleviating neurodegenerative diseases(NDS) and defective reperfusion diseases. It could serve as a potential target for the regulation of autophagy and participate in disease treatment as a meaningful modality. Therefore, exploring DJ-1-regulated autophagy could provide new avenues for future disease treatment.

Keywords:  Autophagic lysosomal pathway; Autophagy; DJ-1; MAM; Oxidative stress

DOI:  https://doi.org/10.1016/j.abb.2023.109672
Acta Histochem. 2023 Jun 19. pii: S0065-1281(23)00075-2. [Epub ahead of print]125(6): 152069

Astaxanthin inhibits oxidative stress and apoptosis in diabetic retinopathy.

Jian Fang, Wuxia Bai, Lina Yang.

   BACKGROUND: The pathophysiology of diabetic retinopathy (DR) is thought to be influenced by oxidative stress. Astaxanthin (ASX) is a natural product with antioxidant effect, but it is not clear whether its mechanism of inhibiting the development of DR is related to anti-oxidation.
METHODS: Rats were intraperitoneally injected with streptozotocin (60 mg/kg) to create DR rat models followed by ASX (20 mg/kg) for 45 days. Retinal tissue was examined by Hematoxylin and Eosin staining. By using Enzyme-linked immunosorbent assay (ELISA), 2,7-Dichlorodrhydrofluorescein diace (DCFH-DA) probes, immunohistochemistry and western blot, it was feasible to evaluate the contents of inflammation-related factors (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and macrophage inhibitory cytokine-1 (MIC-1)), oxidative stress-related indicators (glutathione (GSH), malonic dialdehyde (MDA), glutathione peroxidase (GPx), reactive oxygen species (ROS) and Total antioxidant capacity (T-AOC)), antioxidant enzymes (hemoxgenase-1(HO-1) and Quinone Oxidoreductase 1 (NQO1)), and apoptosis-related proteins (Bcl-2, Bcl2 Associated X Protein (BAX), and cleaved-caspase-3). Additionally, antioxidant proteins downstream of the nuclear factor E2 related factors (Nrf-2) pathway, expression levels of Nrf2/ Kelch-like ECH-associated protein 1(Keap 1) pathway-associated proteins, and nuclear and cytoplasmic levels of Nrf2 were assessed using immunohistochemistry, western blot, or quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS: ASX alleviated retinal tissue damage by increasing overall retina thickness and ganglion cell layer (GCL) cell numbers and exerted the anti-inflammatory, anti-oxidative stress, and anti-apoptosis effects in DR rats. Additionally, ASX could inhibit the expression of Keap1, promote the transport of Nrf2 from cytoplasm to nucleus and facilitate the expressions of HO-1, NQO1, γ-glutamylcysteine synthetase, (γ-GCS) and GPx.
CONCLUSION: ASX exerted antioxidant effects through Nrf2/keap1 pathway, thereby alleviating apoptosis, inflammation, and oxidative stress in retinal tissues of DR rats.

Keywords:  Antioxidation; Astaxanthin; Diabetic retinopathy; Kelch-like ECH-associated protein; Nuclear factor erythroid 2-like 2

DOI:  https://doi.org/10.1016/j.acthis.2023.152069
Exp Eye Res. 2023 Jun 17. pii: S0014-4835(23)00163-X. [Epub ahead of print]233 109542

Retinal pigment epithelium exhibits gene expression and phagocytic activity alterations when exposed to retinoblastoma chemotherapeutics.

Rodrigo Cerna-Chavez, Agata Rozanska, Giulia Lodovica Poretti, Nissim Benvenisty, Manoj Parulekar, Majlinda Lako.

  Retinoblastoma (Rb) is a rare malignant disorder affecting the developing retina of children under the age of five. Chemotherapeutic agents used for treating Rb have been associated with defects of the retinal pigment epithelium (RPE), such as hyperplasia, gliosis, and mottling. Herein, we have developed two pluripotent stem cell (PSC)-RPE models to assess the cytotoxicity of known Rb chemotherapeutics such as Melphalan, Topotecan and TW-37. Our findings demonstrate that these drugs alter the RPE by decreasing the monolayer barrier's trans-epithelial resistance and affecting the cells' phagocytic activity. Transcriptional analyses demonstrate an altered expression of genes involved in melanin and retinol processing, tight junction and apical-basal polarity pathways in both models. When applied within the clinical range, none of the drug treatments caused significant cytotoxic effects, changes to the apical-basal polarity, tight junction network or cell cycle. Together, our results demonstrate that although the most commonly used Rb chemotherapeutic drugs do not cause cytotoxicity in RPE, their application in vitro leads to compromised phagocytosis and strength of the barrier function, in addition to changes in gene expression that could alter the visual cycle in vivo. Our data demonstrate that widely used Rb chemotherapeutic drugs can have a deleterious impact on RPE cells and thus great care has to be exercised with regard to their delivery so the adjacent healthy RPE is not damaged during the course of tumor eradication.

Keywords:  Human embryonic stem cells/ pluripotent stem cells/ human induced pluripotent stem cells/ retinoblastoma/retinal pigment epithelium cells/ chemotherapeutics/ phagocytosis

DOI:  https://doi.org/10.1016/j.exer.2023.109542