Ian A Trounce, Nicole Van Bergen,Vicki Chrysostomou, Rachel Blake,Jonathan Crowston

Purpose:
Impaired mitochondrial function can leadto both energetic crisis and oxidative stress. The mito-chondrial optic neuropathies Leber’s Hereditary OpticNeuropathy (LHON) and Autosomal Dominant OpticAtrophy (ADOA) demonstrate that retinal ganglioncells (RGCs) are the retinal neurons most susceptibleto impaired mitochondrial function or distribution.Mitochondrial function declines with age in post-mitotic cells including neurons, and we hypothesizethat a proportion of glaucoma cases represent anage-related mitochondrial optic neuropathy. Here weinvestigated mitochondrial function in glaucomapatient cells; and retinal ganglion cell function in amouse model of mitochondrial impairment.

Methods:
Mitochondrial oxidative phosphorylation(OXPHOS) capacity was measured in cultured lym-phoblasts of primary open angle glaucoma (POAG)patients using respirometry and maximal ATP pro-duction. A mouse with a mild genetic impairment ofOXPHOS (xenomitochondrial mouse) was stressedwith prolonged diabetes induced by streptozotocintreatment, and retinal function was assessed by elec-troretinogram (ERG).

Results:
POAG patient lymphoblast mitochondriahad significantly impaired maximal ATP produc-tion with OXPHOS complex I substrates. Whenchallenged with the metabolic stress of diabetes,xenomitochondrial mice show greater impairmentof RGC function measured with ERG compared withcontrol animals.

Conclusion:
Subtle mitochondrial dysfunction mayunderlie a sub-group of POAG. A similar degree ofmitochondrial dysfunction in mice leads to measure-able ERG impairment when the animals are stressed bydiabetes. A major challenge for the development ofeffective therapies for preserving the aging optic nerveis to better define how defects in OXPHOS can renderRGCs vulnerable. We believe an improved under-standing of the mitochondrial life-cycle in neuronswith long axons, such as RGCs, and how this cycle isperturbed by bioenergetic defects, will lead to newtherapeutic approaches.