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Nicole J Van Bergen, Jamie E Craig, Alex W Hewitt, Kathryn P Burdon, Shiwani Sharma, Jonathan G Crowston, Ian V Trounce; Mitochondrial Impairments in Primary Open Angle Glaucoma Patient Lymphoblasts. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5035.
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Recently we reported mitochondrial oxidative phosphorylation (OXPHOS) defects in lymphoblasts of Primary Open Angle Glaucoma (POAG) patients (PMID:22427588). This present study confirms our findings in a separate cohort of POAG patients and controls. We further characterise mitochondrial defects by OXPHOS specific activity and determine whether forcing POAG cells to rely on OXPHOS-driven ATP production over glycolysis in galactose media can reveal mitochondrial dysfunction
We assessed mitochondrial activity and cell growth in transformed lymphocytes from POAG patients (n=15) from the well characterised Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and a group of age- and gender-matched controls (n=20). Inclusion criteria were evidence of glaucomatous optic neuropathy (loss of neuroretinal rim & nerve fibre layer), visual field defect and open angles on gonioscopy. Cell growth in glucose and galactose media was assessed by trypan blue exclusion. Cell homogenates were used to measure complexes I and IV and citrate synthase. Digitonin-permeabilised cells were assessed for maximal complex-I and complex-II adenosine triphosphate (ATP) synthesis
There was significant impairment of cell growth when POAG cells were forced to grow in galactose media. There was significantly impaired complex-I and complex-II driven ATP synthesis in POAGs. Detailed OXPHOS enzymology revealed significantly decreased complex-I but not complex-IV or citrate synthase in POAG cells. Results are summarised in the table, significance when P<0.05-students t-test
POAG cells demonstrated impaired complex-I specific activity and ATP synthesis, which may impair cell growth in galactose media when cells are forced to rely on OXPHOS. These findings in an independent POAG cohort support our previous work demonstrating mitochondrial impairments in POAG patients. Mitochondrial defects seen in peripheral cells as previously demonstrated in Leber’s Hereditary Optic Neuropathy are likely present in RGCs. We propose in the presence of a multitude of cellular stressors as seen in the early stages of POAG these mitochondrial impairments may lead to a bioenergetic crisis and increased susceptibility to RGC cell death
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