Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy - PubMed (original) (raw)
Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy
John Guy et al. Ann Neurol. 2002 Nov.
Abstract
A G to A transition at nucleotide 11778 in the ND4 subunit gene of complex I was the first point mutation in the mitochondrial genome linked to a human disease. It causes Leber Hereditary Optic Neuropathy, a disorder with oxidative phosphorylation deficiency. To overcome this defect, we made a synthetic ND4 subunit compatible with the "universal" genetic code and imported it into mitochondria by adding a mitochondrial targeting sequence. For detection we added a FLAG tag. This gene was inserted in an adeno-associated viral vector. The ND4FLAG protein was imported into the mitochondria of cybrids harboring the G11778A mutation, where it increased their survival rate threefold, under restrictive conditions that forced the cells to rely predominantly on oxidative phosphorylation to produce ATP. Since assays of complex I activity were normal in G11778A cybrids we focused on changes in ATP synthesis using complex I substrates. The G11778A cybrids showed a 60% reduction in the rate of ATP synthesis. Relative to mock-transfected G11778A cybrids, complemented G11778A cybrids showed a threefold increase in ATP synthesis, to a level indistinguishable from that in cybrids containing normal mitochondrial DNA. Restoration of respiration by allotopic expression opens the door for gene therapy of Leber Hereditary Optic Neuropathy.
Comment in
- Leber hereditary optic neuropathy: a nuclear solution of a mitochondrial problem.
Larsson NG. Larsson NG. Ann Neurol. 2002 Nov;52(5):529-30. doi: 10.1002/ana.10387. Ann Neurol. 2002. PMID: 12402246 No abstract available.
Similar articles
- The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse.
Qi X, Sun L, Lewin AS, Hauswirth WW, Guy J. Qi X, et al. Invest Ophthalmol Vis Sci. 2007 Jan;48(1):1-10. doi: 10.1167/iovs.06-0789. Invest Ophthalmol Vis Sci. 2007. PMID: 17197509 - Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial.
Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. Koilkonda RD, et al. JAMA Ophthalmol. 2014 Apr 1;132(4):409-20. doi: 10.1001/jamaophthalmol.2013.7630. JAMA Ophthalmol. 2014. PMID: 24457989 Free PMC article. Clinical Trial. - Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice.
Yu H, Ozdemir SS, Koilkonda RD, Chou TH, Porciatti V, Chiodo V, Boye SL, Hauswirth WW, Lewin AS, Guy J. Yu H, et al. Mol Vis. 2012;18:1668-83. Epub 2012 Jun 20. Mol Vis. 2012. PMID: 22773905 Free PMC article. - [LHON (Leber's hereditary optic neuropathy)].
Mashima Y. Mashima Y. Nihon Rinsho. 2002 Apr;60 Suppl 4:282-6. Nihon Rinsho. 2002. PMID: 12013866 Review. Japanese. No abstract available. - The genetics of leber hereditary optic neuropathy--prototype of an inherited optic neuropathy with mitochondrial dysfunction.
Eichhorn-Mulligan K, Cestari DM. Eichhorn-Mulligan K, et al. Semin Ophthalmol. 2008 Jan-Feb;23(1):27-37. doi: 10.1080/08820530701745207. Semin Ophthalmol. 2008. PMID: 18214789 Review.
Cited by
- Hormonal orchestra: mastering mitochondria's role in health and disease.
Al-Suhaimi E, AlQuwaie R, AlSaqabi R, Winarni D, Dewi FRP, AlRubaish AA, Shehzad A, Elaissari A. Al-Suhaimi E, et al. Endocrine. 2024 Aug 22. doi: 10.1007/s12020-024-03967-1. Online ahead of print. Endocrine. 2024. PMID: 39172335 Review. - Leber hereditary optic neuropathy gene therapy.
Lam BL. Lam BL. Curr Opin Ophthalmol. 2024 May 1;35(3):244-251. doi: 10.1097/ICU.0000000000001028. Epub 2023 Dec 20. Curr Opin Ophthalmol. 2024. PMID: 38117686 Review. - Progress in diagnosis and treatment of Leber's hereditary optic neuropathy.
Ma Q, Sun Y, Lei K, Luo W. Ma Q, et al. J Mol Med (Berl). 2024 Jan;102(1):1-10. doi: 10.1007/s00109-023-02389-2. Epub 2023 Nov 20. J Mol Med (Berl). 2024. PMID: 37982904 Review. - Pearls & Oy-sters: Leber Hereditary Optic Neuropathy-Plus Masquerading as Neuromyelitis Optica Spectrum Disorder in a 2-Year-Old Child.
Sunshine A, Mandle QJ, Cabal Herrera AM, Zapanta B, Varma H, Magaña S. Sunshine A, et al. Neurology. 2023 Dec 12;101(24):e2585-e2588. doi: 10.1212/WNL.0000000000207979. Epub 2023 Oct 12. Neurology. 2023. PMID: 37827846 - Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.
Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J. Shamsnajafabadi H, et al. Cells. 2023 Aug 7;12(15):2013. doi: 10.3390/cells12152013. Cells. 2023. PMID: 37566092 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical