Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy
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Date
2015Author
Van Bergen, Nicole J
Crowston, Jonathan G
Craig, Jamie E
Burdon, Kathryn Penelope
Kearns, Lisa S
Sharma, Shiwani
Hewitt, Alex W
Trounce, Ian A
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Show full item recordAbstract
Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized
by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and
increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate
at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial
oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber
Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly
in young adult males, due to complex-I mutations in the mitochondrial genome.
This study directly compares the degree of OXPHOS impairment in POAG and LHON
patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder
complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce
ATP primarily from mitochondrial OXPHOS by switching the media carbon source to
galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls,
whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35
times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts
and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis,
which was 19% decreased in POAG patients and 17% decreased in LHON patients. This
study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in
the majority of aspects the functional defects in POAG were milder than LHON, which could
reflect the milder disease development of POAG. This new evidence places POAG in the
spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic
targets aimed at improving mitochondrial function.