Systems analysis of mitochondrial genome maintenance in physiological context

项目描述/摘要 线粒体DNA（mtDNA）编码对细胞功能至关重要的RNA和蛋白质。但 在动物细胞中，调节mtDNA合成和分离的途径并不好 明白这项工作的目标是确定线粒体DNA的蛋白质组分 类核复合物，研究线粒体复制和动力学如何协调 以保持mtDNA类核分离和丰度的稳态，并探测线粒体DNA中类核的分布。 在体细胞中对突变mtDNA的选择机制。这些实验 将提供基本的见解，维持必要的线粒体， 动物细胞中的染色体以及维持过程如何调节，可能导致 发现和表征调节线粒体DNA遗传的新途径 疾病等位基因我们将采用活细胞和整个动物的尖端显微镜， 蛋白质组学和单细胞转录分析，以询问 与维持mtDNA完整性有关的候选蛋白质。这些实验将 调和线粒体生物学文献中的不一致，提供基本的见解， 线粒体DNA拷贝数控制的机制，并确定新的途径，调节 线粒体功能障碍的组织特异性表现。

Project Description/Summary Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. However, the pathways that regulate mtDNA synthesis and segregation in animal cells are not well understood. The goals of this work are to identify the protein components of mitochondrial DNA nucleoid complexes, to investigate how mitochondrial replication and dynamics are coordinated to homeostatically maintain mtDNA nucleoid segregation and abundance, and to probe the mechanisms underlying selection against mutant mtDNAs in somatic cells. These experiments will provide fundamental insights into the maintenance of the essential mitochondrial chromosome in animal cells and how maintenance processes are regulated, potentially leading to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA disease alleles. We will employ cutting-edge microscopy of living cells and whole animals, proteomics, and single cell transcriptional analyses to interrogate the molecular functions of candidate proteins implicated in the maintenance of mtDNA integrity. These experiments will reconcile inconsistencies in the mitochondrial biology literature, provide fundamental insight into the mechanisms of mtDNA copy number control, and identify novel pathways that regulate the tissue-specific manifestations of mitochondrial dysfunction.