title: Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.
abstract: Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.
authors: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors: Nicole J
authors: NJ
authors: Van Bergen
authors: Jonathan G
authors: JG
authors: Crowston
authors: Lisa S
authors: LS
authors: Kearns
authors: Sandra E
authors: SE
authors: Staffieri
authors: Alex W
authors: AW
authors: Hewitt
authors: Amy C
authors: AC
authors: Cohn
authors: David A
authors: DA
authors: Mackey
authors: Ian A
authors: IA
authors: Trounce
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002457:Cell Extracts; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D029241:Optic Atrophy, Autosomal Dominant / Q000378:metabolism* / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014785:Vision, Ocular / Q000502:physiology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002457:Cell Extracts; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human