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Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy.

Abstract：

PURPOSE:The majority of patients with autosomal dominant optic atrophy (DOA) harbor pathogenic OPA1 mutations and certain missense mutations, mostly within the GTPase domain, have recently been shown to cause multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle. This raises the possibility that the optic neuropathy could be the result of secondary mtDNA defects accumulating within retinal ganglion cells (RGCs). To explore this hypothesis, the authors looked for evidence of mitochondrial dysfunction in a mouse model of DOA and documented the visual and neurologic progression in aging mutant mice. METHODS:Visual function was assessed with a rotating optokinetic (OKN) drum at ages 13 and 18 months and neurologic phenotyping was performed using the primary SHIRPA screen at age 13 months, comparing mutant Opa1(+/)(-) mice with wild-type C57Bl/6 mice. The presence of cytochrome c oxidase (COX) deficiency and multiple mtDNA deletions was investigated in gastrocnemius muscle and eye specimens harvested from 2- and 11-month-old Opa1(+/+) and Opa1(+/)(-) mice. RESULTS:At age 13 months, Opa1(+/)(-) mice had a statistically significant reduction in OKN responses compared to C57Bl/6 controls with both 2 degrees and 8 degrees gratings (P < 0.001). At age 18 months, the difference between the two groups was significant for the 8 degrees grating (P = 0.003) but not for the 2 degrees grating (P = 0.082). Opa1(+/)(-) mice did not exhibit any significant neuromuscular deficits and no COX deficient areas or secondary mtDNA deletions were identified in skeletal muscle or the RGC layer. There was also no evidence of significant mtDNA depletion or proliferation in skeletal muscle from Opa1(+/)(-) mice. CONCLUSIONS:COX deficiency and mtDNA abnormalities do not contribute to optic nerve dysfunction in pure DOA.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Yu-Wai-Man P,Davies VJ,Piechota MJ,Cree LM,Votruba M,Chinnery PF

doi

10.1167/iovs.09-3634

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

4561-6

issue

eissn

0146-0404

issn

1552-5783

pii

iovs.09-3634

journal_volume

pub_type

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Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy.