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Shanjean Lee, Nicole Van Bergen, Evelyn O'Neill, George Kong, Vicki Chrysostomou, Jonathan Crowston, Ian Trounce; Reduction in Complex I-Driven ATP Synthesis in Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5323.
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Leber’s Hereditary Optic Neuropathy (LHON) and primary open-angle glaucoma (POAG) are optic neuropathies with preferential loss of retinal ganglion cells (RGCs). In LHON, defined complex I defects are associated with increased RGC susceptibility to death. Complex I defects in a POLG mouse model of mitochondrial dysfunction also appear to contribute to increased RGC vulnerability to elevated IOP. In this pilot study, we examined complex I and overall mitochondrial function in a small cohort of POAG and control patients.
Complex I and complex II-driven ATP synthesis rates, as well as mitochondrial morphology, cell growth rates, response to mitochondrial toxins, and oxidative phosphorylation (OXPHOS) protein expression were assessed in transformed lymphocytes from POAG patients (n=15) and a group of age- and gender-matched controls (n=15).
POAG lymphoblasts demonstrated significantly decreased rates of mitochondrial ATP synthesis on complex I substrates; furthermore this reduction showed a correlation with clinical disease severity based on visual field defects. Other measures of mitochondrial function, such as gross mitochondrial morphology, cell growth rates, response to mitochondrial toxins, and OXPHOS protein expression revealed no significant differences between the control and POAG cohort.
POAG lymphoblasts exhibit a defect in complex I of the mitochondrial OXPHOS pathway which does not impact cellular function at baseline but leads to decreased ATP synthesis during maximal respiration. In the presence of the multitude of cellular stressors seen in POAG, this mitochondrial defect may contribute to bioenergetic deficiency in the RGCs that results in increased susceptibility to cell death.
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