Mitochondrial abnormalities in patients with primary open-angle glaucoma

Khaled K. Abu-Amero, Jose Morales, Thomas Bosley

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2533-2541
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

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Mitochondrial DNA
Oxidative Stress
Leber's Hereditary Optic Atrophy
Primary Open Angle Glaucoma
Mutation
Retinal Ganglion Cells
Optic Disk
Blindness
Glaucoma
Genes
Axons
Mitochondria
Apoptosis
trabecular meshwork-induced glucocorticoid response protein
Therapeutics

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Mitochondrial abnormalities in patients with primary open-angle glaucoma. / Abu-Amero, Khaled K.; Morales, Jose; Bosley, Thomas.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 6, 06.2006, p. 2533-2541.

Research output: Contribution to journalArticle

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abstract = "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.",
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