The mitochondrion represents a target of reactive oxygen stress and mitochondrial DNA appears to be an early and sensitive marker of this stress. Many human diseases are associated with reactive oxygen, including cancer, heart disease and neurodegenerative diseases. Mitochondria are essential organelles for generating ATP during oxidative phosphorylation. The mitochondrial DNA encodes 13 polypeptides, eleven are involved in electron transport and two serve as subunits of ATP synthase. Damage to mitochondrial DNA is repaired, but prolonged oxidant treatment results in persistent mtDNA damage, loss of mitochondrial function, increase in p21Waf1/CIP, and apoptosis. These observations suggest that mitochondrial injury, specifically DNA damage, is important for reactive oxygen- induced toxicity. We are testing the hypothesis that reactive oxygen species (ROS) generated in the mitochondria result in mtDNA damage, which in turn causes the release of more ROS (O2-?, H2O2, and OH?) that lead to further mitochondrial decline and many degenerative diseases associated with aging. We had previously confirmed this hypothesis using a murine model of Parkinson's disease in which mice are treated with MPTP, a complex I inhibitor. We are continuing these experiments using 3-nitropropionic acid, a complex II inhibitor which produces brain lesions in rodents similar to those observed with Huntington's Disease. We are also examing the role of mitochondrial iron as a partner in Fenton-chemistry-induced mtDNA damage using two different approaches described in more detail below: frataxin mutations in yeast and telomerase expression in human cells

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES061062-05
Application #
6838434
Study Section
(LMG)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ma, Wenjian; Panduri, Vijayalakshmi; Sterling, Joan F et al. (2009) The transition of closely opposed lesions to double-strand breaks during long-patch base excision repair is prevented by the coordinated action of DNA polymerase delta and Rad27/Fen1. Mol Cell Biol 29:1212-21
Wielgus, Albert R; Chignell, Colin F; Miller, David S et al. (2007) Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochem Photobiol 83:706-13
Meyer, Joel N; Boyd, Windy A; Azzam, Gregory A et al. (2007) Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans. Genome Biol 8:R70
Santos, Janine Hertzog; Meyer, Joel N; Van Houten, Bennett (2006) Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet 15:1757-68
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Van Houten, Bennett; Woshner, Victoria; Santos, Janine H (2006) Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst) 5:145-52
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Mandavilli, Bhaskar S; Boldogh, Istvan; Van Houten, Bennett (2005) 3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. Brain Res Mol Brain Res 133:215-23
Santos, Janine Hertzog; Meyer, Joel N; Skorvaga, Milan et al. (2004) Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 3:399-411

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