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Sirt3: A Key Player Against PCB-Induced Mitochondrial Injury

Sirt3：对抗 PCB 引起的线粒体损伤的关键角色

基本信息

批准号：
8496911
负责人：
Nukhet Aykin-Burns
金额：
$ 44.25万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-13 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496911
关键词：
Acetylation Age Antibodies Antioxidants Area Aroclor 1254 Biological Assay Biomedical Research Cell Respiration Cells Chemicals Chronic Complex Couples Deacetylase Drug Metabolic Detoxication Drug Targeting Embryo Environment Environmental Pollutants Enzymes Exhibits Exposure to Fibroblasts Functional disorder Gene Expression Genes Genetic Genomic Instability Glutathione Disulfide Goals Health Health Hazards Hepatotoxicity Homeostasis Hormonal Human Hydrogen Peroxide Immunoprecipitation In Vitro Injury Link Liver Liver Mitochondria Lysine Maintenance Manganese Superoxide Dismutase Mass Spectrum Analysis Measures Membrane Potentials Metabolic Mission Mitochondria Mitotic Cell Cycle Mus Mutate NADH NADP National Institute of Environmental Health Sciences Nature Oligonucleotide Microarrays Oncogenes Oxidation-Reduction Oxidative Stress Oxygen Consumption Phenotype Polychlorinated Biphenyls Post-Translational Protein Processing Process Production Protein Acetylation Proteins Proteomics Radiation Regulation Research Research Activity Role Stress Superoxides Technology Testing Tissues Toxic effect base carcinogenicity experience graduate student human disease in vivo loss of function mitochondrial dysfunction mitochondrial membrane mutant neurotoxicity novel overexpression programs public health relevance respiratory response undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to polychlorinated biphenyls (PCBs) has been associated with a wide range of toxic effects, including hepatotoxicity, carcinogenicity, hormonal disruption, and neurotoxicity. The persistence of PCBs in the environment combined with their "bioaccumulative" nature make PCBs a significant health hazard in highly contaminated areas, even though U.S. production was banned in 1977. Recent research has demonstrated that PCBs and PCB metabolites can increase mitochondrial dysfunction and cause oxidative injury via increases in mitochondrial superoxide and hydrogen peroxide, suggesting that mitochondria are a major target. Sirtuin 3 (Sirt3), which is the major deacetylase in mammalian mitochondria, has been linked to the regulation of the mitochondrial acetylome and activation of several metabolic enzymes (e.g., MnSOD) in response to environmental stresses. Furthermore, loss of function of this mitochondrial fidelity protein appears to enhance the injury processes induced by stress by contributing to aberrant oxidative metabolism and genomic instability in vitro and in vivo. Therefore, the goal of the current application is to determine whether Sirt3 activity can protect against PCB-induced mitochondrial dysfunction, oxidative stress, and tissue injury. In pursuit of this goal, we will rigorously test he hypothesis that Sirt3 function regulates the alterations in the mitochondrial acetylome to maintain oxidative homeostasis in response to PCB-induced mitochondrial injury through the following specific aims. In Aim 1, we will determine if loss of Sirt3 function disrupts the maintenance of the mitochondrial acetylome in response to PCB-induced mitochondrial dysfunction and oxidative stress. Thus, this aim will determine whether loss of Sirt3 function enhances PCB-induced mitochondrial dysfunction (Aim 1a) and oxidative stress (Aim 1b) and whether exposure to PCBs alters the Sirt3 acetylation targets responsible for protecting oxidative homeostasis in the mitochondrial acetylome (Aim 1c). In Aim 2, we will determine if Sirt3 protects against PCB-induced mitochondrial injury by directing MnSOD activity via post-translational modification of critical acetyl lysines (Aim 2a) and whether the changes in acetylation status of critical lysines in MnSOD modulate PCB-induced mitochondrial dysfunction (Aim 2b). In Aim 3, we will determine if the changes in mitochondrial function following PCB exposure result in differential expression of mitochondria-related genes in the livers of Sirt3+/+ and Sirt3-/- mice. Successful completion of these specific aims will contribute to the mechanistic understanding of the role of a mitochondrial fidelity protein, Sirt3, in tissue injury and mitochondrial dysfunction with potential identification of novel targets for pharmacologic manipulation for the health problems arising from PCB exposure. The information to be gained from the proposed studies will also advance the mission of the NIEHS to reduce the burden of human illness and dysfunction from environmental causes. Furthermore, this application will provide biomedical research experience for undergraduate and graduate students in line with the AREA program objectives.