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Thomas Yorio, Donald Daudt, III, Brett Mueller, II; Effects of Sigma-1 Receptors on Mitochondrial Fusion in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4619.
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Mitochondrial dysfunction is implicated in many age-related neurological diseases predisposing susceptible neurons to cell death. Maintaining mitochondrial function and mitochondrial distribution in neurites may enhance RGC function by increasing dendrite outgrowth and dendritic spine formations. The purpose of this study is to investigate the role that sigma agonists play in maintaining mitochondrial stability and distribution in neurites, and synaptogenesis under normal physiological and pathological conditions.
Primary RGCs were purified and transfected with MitoDsRed and subjected to hypoxia for 6 and 8 hours to observe the effects of hypoxia on the mitochondria. Another set of primary RGCs were pretreated with a s1r agonist prior to hypoxic treatment. Additionally, RGCs under normal conditions transfected with MitoDsRed were subjected to live capture experiments to visualize changes in mitochondrial size and distribution under physiological conditions when treated with a s1r agonist. Immunostaining for surface GluR1 (a marker for active postsynaptic receptors) was performed on primary RGCs treated with a s1r agonist overnight.
Mitochondria size and neurite distribution were found to decrease in RGCs after hypoxia, while cells treated with pentazocine were able to maintain mitochondria size and distribution throughout the soma and neurites. Additionally, live capture experiments demonstrated enhancement of mitochondrial size and neurite distribution when primary RGCs were treated with a sigma-1 receptor agonist. Overnight treatment of a sigma-1 receptor agonist was found to upregulate plasma membrane expression of GluR1.
Hypoxia induced mitochondrial fission and decreased mitochondrial distribution in primary RGCs. We hypothesize that s1r agonists exert some of their neuroprotective effects in primary RGCs through their effects on preservation of mitochondrial structure and function. Up regulation of membrane GluR1 expression demonstrates that RGCs treated with a s1r agonist may have a role in synpatogenesis. This also suggest that there may be a link between s1rs, mitochondrial function and increased synaptic formation.
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