The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
The Mutant Human ND4 Subunit of Complex I Induces Optic Neuropathy in the Mouse
Abstract
Purpose To produce a mouse model of Leber hereditary optic neuropathy. Methods A mutant ND4 subunit made compatible with the universal genetic code and containing an arginine-to-histidine substitution at residue 340, or a synthetic normal human ND4 gene was delivered to the mouse visual system. The expression and effects of the mutant ND4 gene on the optic nerve and cultured retinal ganglion cells was assessed by magnetic resonance imaging, immunohistochemistry, and light and transmission electron microscopy. Results The ATPc mitochondrial targeting sequence directed the allotopically expressed mutant human R340H and wild-type ND4FLAG polypeptides into mitochondria. Expression of normal human ND4 in murine mitochondria posed no ocular toxicity. In contrast, the mutant ND4 disrupted mitochondrial cytoarchitecture, elevated reactive oxygen species, induced swelling of the optic nerve head, and induced apoptosis, with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve. Conclusions Allotopic expression of the mutant human R340H ND4 subunit of complex I replicated the hallmarks of human mitochondrial disease in the mouse. In contrast, ocular expression of the wild-type human ND4 subunit in lower mammals appears safe, suggesting that it may be useful for treatment of patients with Leber hereditary optic neuropathy.
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Guy et al. showed that allotopic expression of the human ND4 gene in mice, administered via intravitreal injection, rescues visual dysfunction and prevents the LHON phenotype caused by the G11778A mutation.
“Guy et al. have shown that allotopic expression of the human ND4 gene in mice, administered via intravitreal injection, rescues visual dysfunction and prevents the LHON phenotype caused by the G11778A mutation [125,126].”
From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [125]
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Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy
Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. S., Elsas, L. J., & Nikoskelainen, E. K. (1988) · Science · doi:10.1126/science.3201231 · Cited by 2,440
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Koilkonda, R., Yu, H., Talla, V., Porciatti, V., Feuer, W. J., Hauswirth, W. W., Chiodo, V., Erger, K. E., Boye, S. L., Lewin, A. S., et al. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15388 · Cited by 65
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Koilkonda, R. D. (2010) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2010.135 · Cited by 48
Cwerman-Thibault, H., Augustin, S., Ellouze, S., Sahel, J.-A., & Corral-Debrinski, M. (2014) · Comptes Rendus. Biologies · doi:10.1016/j.crvi.2013.11.011 · Cited by 49
The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics
Saravanan, S., Lewis, C. J., Dixit, B., O’Connor, M. S., Stolzing, A., & Boominathan, A. (2022) · Biomedicines · doi:10.3390/biomedicines10020490 · Cited by 13
Metadata
- Authors
- Qi, X., Sun, L., Lewin, A. S., Hauswirth, W. W., & Guy, J.
- Affiliations
- From the Center for Vision Research, and the1Departments of Ophthalmology,
- From the Center for Vision Research, and the3Molecular Genetics and Microbiology, and
- From the Center for Vision Research, and the1Departments of Ophthalmology,3Molecular Genetics and Microbiology, and
- From the Center for Vision Research, and the1Departments of Ophthalmology,4Neurology, University of Florida, College of Medicine, Gainesville, Florida.
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2007-01-01
- Volume
- 48
- Issue
- 1
- Pages
- 1
- ISSN
- 1552-5783
- Cited by
- 96
- References
- 1
- Language
- en
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