Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy.
OBJECTIVE
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.
Yu-Wai-Man
Patrick
P
Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. patrick.yu-wai-man@ncl.ac.uk
Davies
Vanessa J
VJ
Piechota
Malgorzata J
MJ
Cree
Lynsey M
LM
Votruba
Marcela
M
Chinnery
Patrick F
PF
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology; D020125:Mutation, Missense; D017120:Nystagmus, Optokinetic; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000201:enzymology / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014786:Vision Disorders / Q000235:genetics*
D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse