Mutations in the C. elegans Succinate Dehydrogenase Iron–Sulfur Subunit Promote Superoxide Generation and Premature Aging
| Autor: | Bernard D. Lemire, Jingzhou Huang |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Paraquat Premature aging Protein Conformation SDHB Cell Respiration DNA Mutational Analysis Molecular Sequence Data Respiratory chain Ascorbic Acid macromolecular substances Biology Mitochondrion Antioxidants Animals Genetically Modified Life Expectancy Superoxides Structural Biology Animals Humans Amino Acid Sequence Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology chemistry.chemical_classification Reactive oxygen species Herbicides Succinate dehydrogenase Aging Premature Molecular biology Acetylcysteine Succinate Dehydrogenase Oxidative Stress Protein Subunits Phenotype Mitochondrial respiratory chain Biochemistry chemistry Mutation biology.protein SDHD Reactive Oxygen Species Sequence Alignment |
| Zdroj: | Journal of Molecular Biology. 387:559-569 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2009.02.028 |
| Popis: | The mitochondrial succinate dehydrogenase (SDH) is an iron–sulfur flavoenzyme linking the Krebs cycle and the mitochondrial respiratory chain. Mutations in the human SDHB, SDHC and SDHD genes are responsible for the development of paraganglioma and pheochromocytoma, tumors of the head and neck or the adrenal medulla, respectively. In recent years, SDH has become recognized as a source of reactive oxygen species, which may contribute to tumorigenesis. We have developed a Caenorhabditis elegans model to investigate the molecular and catalytic effects of mutations in the sdhb-1 gene, which encodes the SDH iron–sulfur subunit. We created mutations in Pro211; this residue is located near the site of ubiquinone reduction and is conserved in human SDHB (Pro197), where it is associated with tumorigenesis. Mutant phenotypes ranged from relatively benign to lethal and were characterized by hypersensitivity to oxidative stress, a shortened life span, impaired respiration and overproduction of superoxide. Our data suggest that the SDH ubiquinone-binding site can become a source of superoxide and that the pathological consequences of SDH mutations can be mitigated with antioxidants, such as ascorbate and N -acetyl- l -cysteine. Our work leads to a better understanding of the relationship between genotype and phenotype in respiratory chain mutations and of the mechanisms of aging and tumorigenesis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect