Dataset Information

Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration.

ABSTRACT: Oxidative stress-associated retinal pigment epithelium (RPE) cell death is critically implicated in the pathogenesis of visual dysfunction and blindness of retinal degenerative diseases. Sodium iodate (NaIO3) is an oxidative retinotoxin and causes RPE damage. Previously, we found that NaIO3 can induce human ARPE-19 cell death via inducing mitochondrial fission and mitochondrial dysfunction. Although metformin has been demonstrated to benefit several diseases possibly via AMP-activated protein kinase (AMPK) activation, it remains unknown how AMPK affects retinopathy in NaIO3 model. Therefore, in this study, we compared the effects of metformin and AMPK activator A769662 on NaIO3-induced cellular stress and toxicity. We found that A769662 can protect cells against NaIO3-induced cytotoxicity, while metformin exerts an enhancement in cell death. The mitochondrial reactive oxygen species (ROS) production as well as mitochondrial membrane potential loss induced by NaIO3 were not altered by both agents. In addition, NaIO3-induced cytosolic ROS production, possibly from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and counteracting cell death, was not altered by A769662 and metformin. Notably, NaIO3-induced mitochondrial fission and inhibition of mitochondrial respiration for ATP turnover were reversed by A769662 but not by metformin. In agreement with the changes on mitochondrial morphology, the ERK-Akt signal axis dependent Drp-1 phosphorylation at S616 (an index of mitochondrial fission) under NaIO3 treatment was blocked by A769662, but not by metformin. In summary, NaIO3-induced cell death in ARPE cells primarily comes from mitochondrial dysfunction due to dramatic fission and inhibition of mitochondrial respiration. AMPK activation can exert a protection by restoring mitochondrial respiration and inhibition of ERK/Akt/Drp-1 phosphorylation, leading to a reduction in mitochondrial fission. However, inhibition of respiratory complex I by metformin might deteriorate mitochondrial dysfunction and cell death under NaIO3 stress.

SUBMITTER: Chan CM

PROVIDER: S-EPMC7693507 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration.

Chan Chi-Ming CM Sekar Ponarulselvam P Huang Duen-Yi DY Hsu Shu-Hao SH Lin Wan-Wan WW

Antioxidants (Basel, Switzerland) 20201028 11

Oxidative stress-associated retinal pigment epithelium (RPE) cell death is critically implicated in the pathogenesis of visual dysfunction and blindness of retinal degenerative diseases. Sodium iodate (NaIO<sub>3</sub>) is an oxidative retinotoxin and causes RPE damage. Previously, we found that NaIO<sub>3</sub> can induce human ARPE-19 cell death via inducing mitochondrial fission and mitochondrial dysfunction. Although metformin has been demonstrated to benefit several diseases possibly via AM ...[more]

PMID: 33126710

Similar Datasets

Project description:Mesenchymal stem cells (MSC) are highly regarded as a potential treatment for retinal degenerative disorders like retinitis pigmentosa and age-related macular degeneration. However, donor cell heterogeneity and inconsistent protocols for transplantation have led to varied outcomes in clinical trials. We previously showed that genetically-modifying MSCs to express erythropoietin (MSCEPO) improved its regenerative capabilities in vitro. Hence, in this study, we sought to prove its potential in vivo by transplanting MSCsEPO in a rat retinal degeneration model and analyzing its retinal transcriptome using RNA-Seq. Firstly, MSCsEPO were cultured and expanded before being intravitreally transplanted into the sodium iodate-induced model. After the procedure, electroretinography (ERG) was performed bi-weekly for 30 days. Histological analyses were performed after the ERG assessment. The retina was then harvested for RNA extraction. After mRNA-enrichment and library preparation, paired-end RNA-Seq was performed. Salmon and DESeq2 were used to process the output files. The generated dataset was then analyzed using over-representation (ORA), functional enrichment (GSEA), and pathway topology analysis tools (SPIA) to identify enrichment of key pathways in the experimental groups. The results showed that the MSCEPO-treated group had detectable ERG waves (P <0.05), which were indicative of successful phototransduction. The stem cells were also successfully detected by immunohistochemistry 30 days after intravitreal transplantation. An initial over-representation analysis revealed a snapshot of immune-related pathways in all the groups but was mainly overexpressed in the MSC group. A subsequent GSEA and SPIA analysis later revealed enrichment in a large number of biological processes including phototransduction, regeneration, and cell death (P adj <0.05). Based on these pathways, a set of pro-survival gene expressions were extracted and tabulated. This study provided an in-depth transcriptomic analysis on the MSCEPO-treated retinal degeneration model as well as a profile of pro-survival genes that can be used as candidates for further genetic enhancement studies on stem cells.

Dataset Information

Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration.

Publications

Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets