The long-term goal of this research program is to understand the etiology and pathophysiology of mitochondrial genetic disorders. From this understanding, it may be possible to define the role of mitochondrial respiratory chain dysfunction ina broad range of neurodegenerative disorders. A number of disorders are now known to be caused by mutations in the mitochondrial genome. The pathophysiology most often involves the nervous system although other systems can also be affected, particularly skeletal and cardiac muscle. In addition to the genetically-defined mitochondrial disorders, there is substantial experimental evidence that mitochondrial dysfunction is a pathophysiological component of the late- onset neurodegenerative diseases of Parkinson, Alzheimer, and Huntington. During the previous period of effort, the mitochondrial mutations that are th primary pathogenic factors in Leber hereditary optic neuropathy (LHON), one of a broad group of optic atrophies, have been identified. LHON may now be the neurodegenerative disorder with the best-defined genetic basis. As such, LHON is a good model system by which the mechanisms of neurodegeneration can be elucidated and studied.
One aim of the proposed experiments is to undertake a detailed analysis of the phenotypic effects of primary LHON mutations on cellular energy metabolism. Biochemical and metabolic analyses will be carried out with fibroblast cell cultures to test the effects of primary LHON mutations upon mitochondrial respiratory chain function and citric acid cycle activity. In addition, neuronal cell lines that lack mitochondrial DNA will be developed. These mtDNA-less sublines will then be used for cybrid fusions to enucleated LHON fibroblasts. The resulting cybrids, neuronal cells that carry LHON mutations in their mtDNA, will be used to determine, for the first time, the effects of known pathogenic mitochondrial mutations upon energy metabolism in neuronal cells and upon the expression of neuronal characteristics. The hypothesis will be tested that the pathogenicity of primary LHON mutations is due to an reduction in oxidative phosphorylation. We will also determine whether respiratory chain impairment in these cybrid cells predisposes neuronal cells to neurodegeneration through activation of apoptosis or programmed cell death. Finally, phylogenetic analysis will be used to study the origin and spread of primary LHON mutations throughout the human population during evolution, and the etiological role of secondary LHON mutations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010758-03
Application #
2701408
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1996-05-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
2000-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Chinnery, P F; Andrews, R M; Turnbull, D M et al. (2001) Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet 98:235-43
Howell, N; Ghosh, S S; Fahy, E et al. (2000) Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals. J Neurol Sci 172:6-Jan
Chinnery, P F; Zwijnenburg, P J; Walker, M et al. (1999) Nonrandom tissue distribution of mutant mtDNA. Am J Med Genet 85:498-501
Howell, N (1999) Human mitochondrial diseases: answering questions and questioning answers. Int Rev Cytol 186:49-116
Chinnery, P F; Howell, N; Andrews, R M et al. (1999) Clinical mitochondrial genetics. J Med Genet 36:425-36
Chinnery, P F; Howell, N; Andrews, R M et al. (1999) Mitochondrial DNA analysis: polymorphisms and pathogenicity. J Med Genet 36:505-10
Howell, N (1998) Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve. Vision Res 38:1495-504
Chinnery, P F; Howell, N; Lightowlers, R N et al. (1998) MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 121 ( Pt 10):1889-94
Chinnery, P F; Howell, N; Lightowlers, R N et al. (1998) Genetic counseling and prenatal diagnosis for mtDNA disease. Am J Hum Genet 63:1908-11

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