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Won-Kyu Ju, You Hyun Noh, Keun-Young Kim, Thomas J. Lukas, Robert N. Weinreb; Glutamate Neurotoxicity Induces Mitochondrial Fission-Mediated Mitochondrial Dysfunction in the Optic Nerve Head Astrocytes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3075.
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© ARVO (1962-2015); The Authors (2016-present)
Glutamate neurotoxicity has been linked to mitochondrial dysfunction in neurons in both acute and chronic neurodegenerative disorders including glaucoma. However, there are no reports of addressing whether optic nerve head (ONH) astrocytes are also affected by glutamate neurotoxicity-mediated mitochondrial dysfunction in glaucoma. The goal of this study is to determine whether glutamate neurotoxicity induces mitochondrial fission, ATP depletion and reactive oxygen species (ROS) production in the human ONH astrocytes.
Primary human ONH astrocytes were exposed to N-methyl-D-aspartate (NMDA, 100 µM) for 1hour. GFAP and NMDA receptors (NR1, NR2A, and NR2B) were assessed by immunohistochemistry or Western blot. Mitochondrial fragmentation following pDsRed-Mito transfection was examined by confocal microscopy. Cell viability was assessed by MTT assay. Cellular ATP level and ROS production were measured by a CellTiter-Glo luminescent assay and flow cytometry, respectively.
Immunoreactivities for NMDA receptors (NR1, NR2A, and NR2B) was colocalized with GFAP in the normal human ONH astrocytes. NMDA treatment induces mitochondrial fission, characterized by the conversion of tubular fused mitochondria into isolated small organelles, at 5 hours after recovery in the normal human ONH astrocytes. NMDA treatment also resulted in a significant reduction of cellular ATP by 0.66 ± 0.03-fold. In contrast, NMDA treatment significantly increased ROS production in the normal human ONH astrocytes.
These results suggest that NDMA receptor activation/mitochondrial fission-mediated mitochondrial dysfunction may be an important mechanism in the ONH astrocyte degeneration of glaucoma.
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