mtDNA Rearrangements in Human Development and Disease

人类发育和疾病中的线粒体 DNA 重排

• 批准号: 7031067
• 负责人: MICHAEL P KING
• 金额: $ 26.93万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031067
• 关键词: DNA damage; cell line; gene conversion; gene deletion mutation; gene rearrangement; genetic markers; mitochondrial DNA; molecular pathology; point mutation; polymerase chain reaction; DNA damage; cell line; gene conversion; gene deletion mutation; gene rearrangement; genetic markers; mitochondrial DNA; molecular pathology; point mutation; polymerase chain reaction

DESCRIPTION (provided by applicant): Mitochondria are unusual among the organelles of a eukaryotic cell in that they possess their own genome, the mtDNA. The replication and transcription of mtDNA and the translation of the mtDNA-encoded proteins is essential for the production of ATP by oxidative phosphorylation. Evolutionary analyses and molecular studies of human mtDNA indicate that recombination of human mtDNA occurs. Recombination of mtDNA occurs at low levels in healthy individuals and results in the accumulation of mtDNA rearrangements, whose levels increase with age. At high levels, mtDNA rearrangements can result in mitochondrial dysfunction and human disease. It is difficult to observe mtDNA recombination experimentally in cells because of the lack of appropriate mtDNA markers to detect recombination. A model system is described here that uses uniquely marked human mtDNAs that permit the detection of inter-molecular and intra-molecular recombinant mtDNAs. This system of analysis will be used to identify the products of mtDNA recombination and to determine their rates of formation. Subsequently, the mechanisms by which recombinant mtDNAs are formed in cells will be investigated. These investigations are likely to lead to significant insights into the mechanism for formation of pathogenic mtDNA rearrangements, as well as into fundamental cellular processes involving mtDNA including mtDNA maintenance, replication, and repair mechanisms.

描述（由申请人提供）：线粒体在真核细胞的细胞器中是不寻常的，因为它们具有自己的基因组mtDNA。 mtDNA的复制和转录以及mtDNA编码蛋白的翻译对于通过氧化磷酸化生产ATP至关重要。对人mtDNA的进化分析和分子研究表明，人mtDNA的重组发生。 MTDNA的重组发生在健康个体中的低水平，并导致mtDNA重排的积累，其水平随着年龄的增长而增加。在高水平上，mtDNA重排可能导致线粒体功能障碍和人类疾病。由于缺乏合适的mtDNA标记来检测重组，很难在细胞中实验观察mtDNA重组。这里描述了模型系统，该模型系统使用了唯一标记的人MTDNA，该模型系统允许检测分子间和分子内重组MTDNA。该分析系统将用于识别mtDNA重组的产物并确定其形成速率。随后，将研究在细胞中形成重组MTDNA的机制。这些研究可能会导致对形成致病MTDNA重排的机制，以及涉及MTDNA的基本细胞过程，包括MTDNA维持，复制和修复机制。