Mitochondria may play key role in glaucoma pathogenesis

This landmark study by an Italian research group presents direct evidence for an endogenous mitochondrial source of reactive oxygen species. They conducted this case-control study to analyze the frequency of mitochondrial DNA damage in patients with primary open-angle glaucoma. It is believed to be the largest study performed analyzing genetic polymorphisms and molecular alterations directly in the trabecular meshwork.

Oxidative damage in the trabecular meshwork has long been suspected of playing an important role in the development of glaucoma. Although potential sources of oxidative stress, such as cigarette smoke or light/radiation, have been postulated, direct evidence for a source of reactive oxygen species in glaucoma has been lacking. Since no environmental risk factor for glaucoma is recognized, the authors focused their attention on mitochondria, the main endogenous source of reactive oxygen species.

They evaluated mitochondrial damage by analyzing a common mitochondrial DNA deletion by real-time polymerase chain reaction in the trabecular meshwork. The authors collected trabecular network specimens from 79 patients with primary open-angle glaucoma at the time of surgery and 156 unaffected matched controls. Polymorphisms of genes encoding for antioxidant defenses (GSTM1), repair of oxidative DNA damage (OGG1) and apoptosis (FAS) were also tested.

The authors detected a statistically significant five-fold increase in the level of mitochondrial deletion in the trabecular network of glaucoma patients compared with controls. This is a common marker of mitochondrial DNA damage associated with oxidative stress. In addition, the researchers found a nearly five-fold decrease in the number of mitochondria per trabecular meshwork cell and a dramatic decrease in trabecular meshwork cell numbers compared with control cornea donor specimens. The changes in the mitochondrial DNA marker were not found in adjacent iris tissue. Subjects with deficient antioxidant defenses due to a common polymorphism in the GSTM1 gene had particularly increased levels of the marker for mitochondrial DNA damage.

The study findings strongly suggest that mitochondria play an important role in the pathogenesis of glaucoma. Oxidative damage in the trabecular meshwork induces mitochondrial damage and triggers apoptotic loss of trabecular meshwork cells. This may lead to impaired aqueous humor outflow and elevated intraocular pressure. The results indicate that primary open-angle glaucoma patients bear a genetic predisposition to oxidative stress that contributes to mitochondrial DNA damage and apoptosis.