June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age-related Macular Degeneration, Role of Homocysteine
Author Affiliations & Notes
  • Rana Abdelkarim
    Eye research Instiute, Oakland University, Rochester, Michigan, United States
  • LALITH KUMAR VENKAREDDY
    Eye research Instiute, Oakland University, Rochester, Michigan, United States
  • Paul Negoita
    Eye research Instiute, Oakland University, Rochester, Michigan, United States
  • Amany A Tawfik
    Eye research Instiute, Oakland University, Rochester, Michigan, United States
  • Footnotes
    Commercial Relationships   Rana Abdelkarim None; LALITH KUMAR VENKAREDDY None; Paul Negoita None; Amany Tawfik None
  • Footnotes
    Support  -
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3882. doi:
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      Rana Abdelkarim, LALITH KUMAR VENKAREDDY, Paul Negoita, Amany A Tawfik; Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age-related Macular Degeneration, Role of Homocysteine. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3882.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is the most common cause of vision loss
among elderly populations. Many studies reported elevated homocysteine (Hcy), also
known as hyperhomocysteinemia (HHcy) in patients with AMD. We previously
confirmed HHcy in AMD patients and reported altered retinal pigment epithelial cells
(RPE) structure and function by HHcy. Furthermore, we reported activated Oxidative
and endoplasmic reticulum (ER) stresses in the retina of a mouse model of HHcy.
Mitochondria plays fundamental roles in generating energy and their dysfunction has
been suggested in the pathogenesis of AMD. Impaired mitochondrial dysfunction
decreases ATP production resulting in increased reactive oxygen species (ROS),
adding stress to the ER, and inducing RPE alteration that was reported in AMD patients.
Although the principal role of ER stress is to protect cells, however, chronic
exposure to oxidative stress and inflammation in patients with AMD turns this defensive
response into a destructive process that induces cell death and enhances mitochondrial
dysfunction, oxidative stress, and inflammation generating a perpetual cycle that results
in development and progression AMD. This study is evaluating ROS and ER
stress induced by mitochondrial dysfunction in RPE cells under HHcy as a possible
mechanism and therapeutic approach to AMD.

Methods : Human retinal pigment epithelial cells (ARPE-19) treated with/without different
concentrations of Hcy were evaluated for energy production using
mitochondrial stress test, ROS formation using Cell-Rox, and ER stress markers (BIP,
PERK, ATF4, and CHOP) using qPCR and protein analysis. Furthermore, ROS and ER
stress markers were evaluated in primary RPE cells isolated from a mouse model of
HHcy (CBS). Additionally, cell death was confirmed by
measuring of death marker caspase-3.

Results : Hcy induced glycolysis in ARPE-19 cells indicated by (ECAR) and reduced
mitochondrial respiration, indicated by (OCR). Both RPE-19 treated with Hcy and
primary RPE (cbs +/- ) revealed activation of ROS and ER stress compared to controls.
Also, HHcy activated RPE cell death indicated by significant elevation of caspase-3.

Conclusions : HHcy-induced mitochondrial dysfunction results in the activation of oxidative stress and
ER stress with subsequent alteration and death of RPE cells. Targeting Oxidative/ER
stresses provide insight into possible mechanisms and therapeutic approach for AMD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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