title: Increase in mitochondrial DNA mutations impairs retinal function and renders the retina vulnerable to injury.
abstract: Mouse models that accumulate high levels of mitochondrial DNA (mtDNA) mutations owing to impairments in mitochondrial polymerase γ (PolG) proofreading function have been shown to develop phenotypes consistent with accelerated aging. As increase in mtDNA mutations and aging are risk factors for neurodegenerative diseases, we sought to determine whether increase in mtDNA mutations renders neurons more vulnerable to injury. We therefore examined the in vivo functional activity of retinal neurons and their ability to cope with stress in transgenic mice harboring a neural-targeted mutant PolG gene with an impaired proofreading capability (Kasahara, et al. (2006) Mol Psychiatry11(6):577-93, 523). We confirmed that the retina of these transgenic mice have increased mtDNA deletions and point mutations and decreased expression of mitochondrial oxidative phosphorylation enzymes. Associated with these changes, the PolG transgenic mice demonstrated accelerated age-related loss in retinal function as measured by dark-adapted electroretinogram, particularly in the inner and middle retina. Furthermore, the retinal ganglion cell-dominant inner retinal function in PolG transgenic mice showed greater vulnerability to injury induced by raised intraocular pressure, an insult known to produce mechanical, metabolic, and oxidative stress in the retina. These findings indicate that an accumulation of mtDNA mutations is associated with impairment in neural function and reduced capacity of neurons to resist external stress in vivo, suggesting a potential mechanism whereby aging central nervous system can become more vulnerable to neurodegeneration.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors.forename: Yu X G
authors.initials: YX
authors.lastname: Kong
authors.forename: Nicole
authors.initials: N
authors.lastname: Van Bergen
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.forename: Bang V
authors.initials: BV
authors.lastname: Bui
authors.forename: Vicki
authors.initials: V
authors.lastname: Chrysostomou
authors.forename: Hayley
authors.initials: H
authors.lastname: Waugh
authors.forename: Algis
authors.initials: A
authors.lastname: Vingrys
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Crowston
mesh_terms: D000818:Animals; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D007429:Intraocular Pressure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000502:physiology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D012160:Retina / Q000378:metabolism / Q000503:physiopathology*; D013312:Stress, Physiological
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse