Document Detail


Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation.
MedLine Citation:
PMID:  17296905     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To explore a treatment paradigm for Leber hereditary optic neuropathy (LHON), we augmented mitochondrial antioxidant defenses to rescue cells with the G11778A mutation in mitochondrial DNA. METHODS: Cells homoplasmic for the G11778A mutation in mitochondrial DNA were infected with an adeno-associated viral vector containing the human mitochondrial superoxide dismutase (SOD2) gene. Control cells were infected with an adeno-associated viral (AAV) vector expressing the green fluorescent protein (GFP). Two days later, the high-glucose culture medium was exchanged for a glucose-free medium containing galactose. After 1 or 2 days, cellular production of superoxide was assessed using the fluorescent probe dihydroethidium, and we used TUNEL (terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling) staining to detect apoptotic nuclei. The effect of SOD2 on LHON cell survival was quantitated after 2 or 3 days. RESULTS: Comparisons of AAV-SOD2-infected LHON cells relative to control cells infected with AAV-green fluorescent protein showed increased expression of mitochondrial SOD that attenuated superoxide-induced fluorescence by 26% (P = .003) and suppressed TUNEL-induced fluorescence by 21% (P = .048) after 2 days of growth in galactose medium, when cell survival increased by 25% (P=.05). After 3 days in galactose medium, SOD2 increased LHON survival by 89% (P = .006) relative to controls. CONCLUSION: Protection against mitochondrial oxidative stress may be useful for treatment of LHON. CLINICAL RELEVANCE: Gene therapy with antioxidant genes may protect patients with LHON against visual loss.
Authors:
Xiaoping Qi; Liang Sun; William W Hauswirth; Alfred S Lewin; John Guy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Archives of ophthalmology     Volume:  125     ISSN:  0003-9950     ISO Abbreviation:  Arch. Ophthalmol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-13     Completed Date:  2007-02-27     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  7706534     Medline TA:  Arch Ophthalmol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  268-72     Citation Subset:  AIM; IM    
Affiliation:
Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
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MeSH Terms
Descriptor/Qualifier:
Antioxidants / metabolism*
Apoptosis
Cell Survival
Cells, Cultured
DNA, Mitochondrial / genetics*
Dependovirus / genetics
Gene Expression Regulation, Enzymologic / physiology
Gene Therapy*
Genetic Vectors
Green Fluorescent Proteins / genetics
Humans
In Situ Nick-End Labeling
Microscopy, Fluorescence
Mitochondria / metabolism*
Optic Atrophy, Hereditary, Leber / enzymology,  therapy*
Oxidative Stress
Plasmids
Reactive Oxygen Species / metabolism
Superoxide Dismutase / genetics*
Superoxides / toxicity
Transfection
Grant Support
ID/Acronym/Agency:
EY 12355/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/DNA, Mitochondrial; 0/Reactive Oxygen Species; 11062-77-4/Superoxides; 147336-22-9/Green Fluorescent Proteins; EC 1.15.1.1/Superoxide Dismutase; EC 1.15.1.1/superoxide dismutase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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