June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Endoplasmic Reticulum-Mitochondria crosstalk in Retinal Pigment Epithelium dysfunction: Implications for age-related retinal diseases
Author Affiliations & Notes
  • Thangal Yumnamcha
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Ebrahim Abdul Shukkur
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Elizabeth A Berger
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Lalit S Pukhrambam
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Ahmed Ibrahim
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
    Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Footnotes
    Commercial Relationships   Thangal Yumnamcha None; Ebrahim Abdul Shukkur None; Elizabeth Berger None; Lalit S Pukhrambam None; Ahmed Ibrahim None
  • Footnotes
    Support  American Heart Association Grant 18CDA34080403, NIH core grant P30EY004068 to the Department of Ophthalmology, Visual and Anatomical Sciences (OVAS), NIH/NEI EY023992 to LPS and a Research to Prevent Blindness unrestricted grant to the Department of OVAS, Wayne State University, Detroit, MI, USA.
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 789 – F0348. doi:
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    • Get Citation

      Thangal Yumnamcha, Ebrahim Abdul Shukkur, Elizabeth A Berger, Lalit S Pukhrambam, Ahmed Ibrahim; Endoplasmic Reticulum-Mitochondria crosstalk in Retinal Pigment Epithelium dysfunction: Implications for age-related retinal diseases. Invest. Ophthalmol. Vis. Sci. 2022;63(7):789 – F0348.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Purpose: Endoplasmic reticulum (ER) stress is linked with several retinal degenerative diseases including age-related macular degeneration (AMD). Chronic ER stress during ageing leads to retinal pigment epithelium (RPE) dysfunction, which is a hallmark of AMD. However, the role of mitochondria in ER stress-induced RPE dysfunction remains poorly investigated. Therefore, the objective of the present study is to explore the crosstalk between the ER and mitochondria (MT) in ER stress-induced RPE dysfunction and cell death.

Methods : Methods: A human RPE cell line (ARPE-19) was treated with an ER stress inducer (tunicamycin (TM), 1µg/mL,) for 48 h. Protective effect of various pharmacological inhibitors and mitochondrial targeted antioxidant, MitoQ, were assessed. Mitochondrial ROS (mt-ROS), membrane potential (Δψm), and intracellular ATP level were measured by Mitosox, JC-1, and ATP assays, respectively. Cell death was determined by lactate dehydrogenase (LDH) leakage. Barrier integrity was assessed by electric cell-substrate impedance sensing (ECIS) system. qPCR and western blot were performed to determine ER stress and apoptotic markers expression. Statistical analysis was performed using ANOVA or Student's t test.

Results : Results: Treatment of ARPE-19 cells with TM significantly upregulated several ER stress markers gene, including XBP1s, ATF4, CHOP and PDI. Furthermore, TM-treatment resulted in an increase in mt-ROS, decreased Δψm, less ATP, and cell death. Interestingly, JNK kinase inhibitor pretreatment attenuated TM-induced cell death. Bid, a mitochondrial proapoptotic protein, was also increased in TM-treated ARPE-19 cells and pretreatment with BI-6C9, an inhibitor of Bid, reduced TM-induced cell death. Finally, MitoQ pretreatment attenuated disruption of membrane integrity and cell death induced by TM.

Conclusions : Conclusions: Our results demonstrate that ER stress induces apoptosis in ARPE-19 cells by causing mitochondrial damage. We further show that blocking mitochondrial apoptotic pathway or addition of mitochondria-targeted antioxidant have a protective effect against ER stress-induced cell death.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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