Mitochondrial abnormalities in patients with primary open-angle glaucoma

PURPOSE: Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head. METHODS: In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed. RESULTS: Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001). CONCLUSIONS: These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities.