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Abstract #73158 Published in IGR 18-4
Sigma-1 Receptor Regulates Mitochondrial Function in Glucose- and Oxygen-Deprived Retinal Ganglion Cells
Ellis DZ; Li L; Park Y; He S; Mueller B; Yorio TInvestigative Ophthalmology and Visual Science 2017; 58: 2755-2764
PURPOSE: Understanding the role of mitochondria in retinal ganglion cells (RGCs) is relevant to human disease as studies have shown mitochondrial abnormalities in primary open-angle glaucoma patients. This study seeks to determine the effects of the sigma-1 receptor (σ-1r) and its agonists on mitochondrial function in oxygen- and glucose- deprived (OGD) purified neonatal RGCs. METHODS: Retinal ganglion cells were isolated from rat pups and subjected to OGD in varying conditions in the presence or absence of σ-1r agonist and antagonist and following addition of an AAV2-σ-1r vector that was used to increase σ-1r expression. Western blots and immunofluorescence microscopy validated findings. Mitochondrial function was determined by measuring mitochondrial membrane potential (Δψm) using the dye, fluorescence tetraethylbenzimidazolylcarbocyanineiodide (JC-1), and determination of cytochrome c oxidase activity using a cytochrome c oxidase assay kit. Caspase 3 and 7 activities were also measured using a luminescent assay kit. RESULTS: Oxygen and glucose deprivation in RGCs resulted in decreased mitochondrial membrane potential and cytochrome c oxidase activity when compared with normoxic RGCs. σ-1r agonists or overexpression of the σ-1r restored the mitochondrial membrane potential comparable to normoxic conditions, while σ-1r antagonists abolished these effects. Oxygen and glucose depreavtation induced decreases in cytochrome c activity were partially restored by overexpression or activation of σ-1r. Caspase activity was increased in response to OGD and was decreased by the addition of σ-1r agonist, pentazocine, and following σ-1r overexpression. CONCLUSIONS: These data suggest that activation and/or overexpression of σ-1r restores RGCs mitochondrial function following OGD and that mitochondrial function is vital to the function of RGCs.
Department of Pharmaceutical Sciences, University of North Texas Systems College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, United States 2North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States.
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