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Editors Selection IGR 15-4

Basic Research - RGC: Mitochondrial dysfunction predisposes to RGC loss

Comment by Jonathan Crowston on:

48769 A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics, Nguyen D; Alavi MV; Kim KY et al., Cell Death and Disease, 2011; 2: e240

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Mutations in the OPA1 gene account for a significant proportion of Autosomal Dominant Optic Atrophy cases (ADOA). The OPA1 protein is expressed in the inner mitochondrial membrane and plays a role in maintaining mitochondrial fusion, which promotes efficient fuel production by mitochondria. In the presence of OPA1 mutations, mitochondria undergo fission and this predisposes to RGC loss. The mechanisms underlying RGC death in this setting are still not clear. In this manuscript, Nguyen and colleagues report an elegant detailed ana lysis of retinal changes in a genetically modified mouse harboring a deficiency in OPA1. The OPA1^enu/+ mouse demonstrated progressive loss of RGC associated with increased activation of astrocytes and microglia, reduced levels of mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) and increased levels of the NMDA receptor s (NR1, 2A and 2B). In addition, RGCs in this mouse had a pro-apoptotic propensity expressing relatively higher levels of proapoptotic Bax and phosphorylated Bad with lower anti-apoptotic Bcl-xL. These findings suggest that mitochondrial fission in the presence of OPA1 deficiency predisposes to oxidative stress and excitotoxicity. As excitotoxic injury and oxidative stress per se can promote mitochondrial fission and dysfunction, the authors propose that in the presence of on OPA1 mutation, a vicious cycle is established that predisposes to neurodegeneration. Further work is now required to test this hypothesis directly and demonstrate that perturbing the vicious cycle in-vivo can protect RGCs.

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