Mitochondrial oxidative phosphorylation in autosomal dominant optic atrophy.
BACKGROUND
Autosomal dominant optic atrophy (ADOA), a form of progressive bilateral blindness due to loss of retinal ganglion cells and optic nerve deterioration, arises predominantly from mutations in the nuclear gene for the mitochondrial GTPase, OPA1. OPA1 localizes to mitochondrial cristae in the inner membrane where electron transport chain complexes are enriched. While OPA1 has been characterized for its role in mitochondrial cristae structure and organelle fusion, possible effects of OPA1 on mitochondrial function have not been determined.


RESULTS
Mitochondria from six ADOA patients bearing OPA1 mutations and ten ADOA patients with unidentified gene mutations were studied for respiratory capacity and electron transport complex function. Results suggest that the nuclear DNA mutations that give rise to ADOA in our patient population do not alter mitochondrial electron transport.


CONCLUSIONS
We conclude that the pathophysiology of ADOA likely stems from the role of OPA1 in mitochondrial structure or fusion and not from OPA1 support of oxidative phosphorylation.
Mayorov
Vladimir I
VI
Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA. mayorov_vi@mercer.edu
Lowrey
Angela J
AJ
Biousse
Valerie
V
Newman
Nancy J
NJ
Cline
Susan D
SD
Brown
Michael D
MD
D004579:Electron Transport / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation
D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
J Cell Biol. 2007 Aug 27;178(5):749-55
17709429
J Biol Chem. 2003 Mar 7;278(10):7743-6
12509422
Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4288-94
16249510
J Biol Chem. 2004 Apr 30;279(18):18792-8
14970223
Hum Mol Genet. 2001 Jun 15;10(13):1369-78
11440989
Hum Mutat. 2008 Jan;29(1):106-12
17722006
Nat Genet. 2000 Oct;26(2):211-5
11017080
Acta Ophthalmol Scand. 2005 Jun;83(3):337-46
15948788
J Biol Chem. 2000 Dec 22;275(51):39831-6
10976107
Am J Med Genet. 2001 Dec 15;104(4):331-8
11754070
Hum Mol Genet. 1999;8(10):1893-900
10469842
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R283-9
16244327
Dev Cell. 2006 Nov;11(5):592-4
17084350
Traffic. 2001 Apr;2(4):235-44
11285133
J Biol Chem. 2002 Nov 15;277(46):43553-6
12364341
Hum Genet. 2002 Feb;110(2):130-8
11935318
Genet Med. 2006 Apr;8(4):217-25
16617242
Hum Genet. 2001 Dec;109(6):584-91
11810270
Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1715-24
12036970
Mol Biol Cell. 2004 Nov;15(11):5001-11
15356267
Brain. 2008 Feb;131(Pt 2):338-51
18158317
Mol Cell Biol. 1996 Mar;16(3):771-7
8622678
Cell. 2006 Oct 20;127(2):383-95
17055438
Cell. 2006 Jul 14;126(1):27-9
16839872
Hum Mutat. 2005 May;25(5):423-8
15832306
Hum Mol Genet. 2001 Jun 15;10(13):1359-68
11440988
Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15927-32
15509649
Biosci Rep. 2007 Jun;27(1-3):173-84
17479363
Methods Enzymol. 1996;264:484-509
8965721
Nat Genet. 2000 Oct;26(2):207-10
11017079
Annu Rev Biochem. 2007;76:751-80
17362197
Brain. 2008 Feb;131(Pt 2):352-67
18222991
Ann Neurol. 2004 Nov;56(5):719-23
15505825
EMBO J. 2006 Jul 12;25(13):2966-77
16778770