Models to study the impact of mitochondrial dysfunction on neurodegeneration

M. Mcmanus Children's Hospital of Philadelphia, Pathology, Philadelphia, United States Summary: Mitochondrial dysfunction(definition) is one of the greatest common factors in ophthalmological diseases characterized by the selective loss of retinal ganglion cells (RGCs). Interestingly, the mitochondrial impairment appears to specifically involve OXPHOS complex I (C-I) inhibition, which correlates with the age of onset and severity of disease. The complex genetics and bioenergetic etiology of these diseases have stalled the development of effective animal models and therapies, until now. We have created mice with mtDNA and nDNA alterations specific to human optic atrophy. The first, C-I mtDNA ND6P25L mutant mouse adequately recapitulates LHON. The ND6P25L mutation causes a ˜30% reduction in C-I activity and increased mitochondrial ROS without affecting ATP production. Increased oxidative stress precedes ERG abnormalities in ND6P25L mice, suggesting RGC death is due to increased oxidative stress. As such, we have developed a noninvasive method for quantitative analysis of oxidative stress in vivo, which we propose as a predictive biomarker for optic neuropathy. With these new models and techniques, we are in an unprecedented position to develop preventative mitochondria-targeted therapeutics for direct translation to the clinic.