It has been shown in recent years that structural and functional defects of mitochondrial proton-translocating NADH-ubiquinone oxidoreductase (complex I) are involved in many human diseases. These diseases include Leber's hereditary optic neuropathy, Parkinson's disease, dystonia, severe lactic acidosis, various forms of encephalomyopathies, and possibly Huntington's disease. Dysfunction of complex I presents three problems: (1) Impairment of the ability of the respiratory chain to oxidize NADH back to NAD4 which is required, among other things, for operation of the citric acid cycle and fatty acid oxidation enzymes. (2) Impairment of the ability of this enzyme to pump protons, resulting in a decrease in the rate of ATP synthesis. (3) Production of superoxide radicals, causing mitochondrial DNA (mtDNA) mutation, lipid peroxidation, and protein denaturation. Mammalian complex I is composed of at least 41 unlike subunits and has the most intricate structure among the membrane-bound enzyme complexes. Of these subunits, seven are encoded by mtDNA and synthesized within the mitochondrion, and other are cytoribosomal products. At present, mutations and deletions of the subunits encoded by MtDNA are not correctable, and mutations of plural subunits encoded by nuclear ONA (nDNA) are difficult to repair. The overall goal of this grant application is to find a remedy for the diseases that result from dysfunction of complex I.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053244-03
Application #
2906133
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Laughlin, Maren R
Project Start
1997-06-01
Project End
2000-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Marella, Mathieu; Seo, Byoung Boo; Nakamaru-Ogiso, Eiko et al. (2008) Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS One 3:e1433
Sherer, Todd B; Richardson, Jason R; Testa, Claudia M et al. (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson's disease. J Neurochem 100:1469-79
Richardson, Jason R; Caudle, W Michael; Guillot, Thomas S et al. (2007) Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicol Sci 95:196-204
Marella, Mathieu; Seo, Byoung Boo; Matsuno-Yagi, Akemi et al. (2007) Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line. J Biol Chem 282:24146-56

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