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Dorette Z. Ellis, Linya Li, Yong Park, Shaoqing He, Brett Mueller, Thomas Yorio; Sigma-1 Receptor Regulates Mitochondrial Function in Glucose- and Oxygen-Deprived Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2017;58(5):2755-2764. doi: 10.1167/iovs.16-19199.
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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.
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.
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.
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.
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