Adaptive Physiology of mtDNA Longevity Mutations

线粒体DNA长寿突变的适应性生理学

• 批准号: 7093183
• 负责人: Douglas C Wallace
• 金额: $ 39.02万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093183
• 关键词: aerobiosis; cell cycle; cell population study; clinical research; cytoprotection; electron transport; environmental adaptation; free radical oxygen; gene environment interaction; gene mutation; genetic screening; genetically modified animals; geographic difference; human subject; laboratory mouse; longevity; mitochondria; mitochondrial DNA; nucleic acid sequence; oxidative phosphorylation; oxidative stress; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Several surveys of centenarians from Eurasia have revealed that specific mitochondrial DNA (mtDNA) lineages are associated with reduced neurodegenerative disease and increased longevity. These same Eurasia mtDNA lineages (haplogroups) show striking regional localization which we have recently discovered is the result of mtDNA missense mutations that permitted the founders of these lineages to adapt to the increasingly colder climates as they migrated out of Africa into Eurasia and then into Siberia and North America. We hypothesize that missense mutations are protective of neurodegenerative diseases and aging because they partially uncouple mitochondrial oxidative phosporylation (OXPHOS). This increased heat production, but it is protective of aging because it keeps the electron transport chain oxidized thus reducing mitochondrial reactive oxygen (ROS) species production and oxidative damage. To test this hypothesis, we propose to determine if Native American mtDNA acquired new adaptive mutations as they migrated southward from the arctic to tropical South America. We will also correlate skeletal muscle mitochondrial OXPHOS enzyme levels with mtDNA haplogroups and correlate the biochemical defects with alterations in muscle energetics as assessed by magnetic resonance and Near Infra-red spectroscopy. Then transfer the various mtDNA haplogroups into the same ?o lymphoblastoid cell nuclear background and test the resulting cybrids for differences in mitochondrial enzymes, OXPHOS coupling, ROS production, mitochondrial and cellular oxidative damage, hyper-activation of the mitochondrial permeability transition pore (mtPTP) and changes in MITOCHIP gene expression profile. We will determine the extent of somatic mtDNA control region (CR) and rearrangement mutations that accumulate in the cells and tissues of subjects with different climatic adaptive mutations. Finally, we will sequence the mtDNAs of mice that have adapted to climatic extremes. If they also harbor adaptive mtDNA mutations, then use female ES cell line to introduce the variant mtDNA lineages into the mouse germ line. These mice will be bred the progeny tested for their sensitivity to heat and cold, the biochemistry and physiology of their mitochondria, their exercise physiology, and their longevity.

描述（由申请人提供）：对欧亚大陆百岁老人的多项调查显示，特定的线粒体 DNA (mtDNA) 谱系与减少神经退行性疾病和延长寿命有关。这些相同的欧亚大陆 mtDNA 谱系（单倍群）显示出惊人的区域定位，我们最近发现这是 mtDNA 错义突变的结果，使这些谱系的创建者在从非洲迁徙到欧亚大陆，然后进入西伯利亚和北美时能够适应日益寒冷的气候。我们假设错义突变可以保护神经退行性疾病和衰老，因为它们部分解开线粒体氧化磷酸化（OXPHOS）。这增加了热量的产生，但它可以防止衰老，因为它使电子传递链保持氧化，从而减少线粒体活性氧（ROS）物质的产生和氧化损伤。为了检验这一假设，我们建议确定美洲原住民线粒体 DNA 在从北极向南迁徙到南美洲热带地区时是否获得了新的适应性突变。我们还将骨骼肌线粒体 OXPHOS 酶水平与 mtDNA 单倍群相关联，并将生化缺陷与通过磁共振和近红外光谱评估的肌肉能量学变化相关联。然后将各种mtDNA单倍群转移到相同的淋巴母细胞核背景中，并测试所得胞质杂种的线粒体酶差异、OXPHOS偶联、ROS产生、线粒体和细胞氧化损伤、线粒体通透性转换孔（mtPTP）的过度激活以及MITOCHIP基因表达谱的变化。我们将确定具有不同气候适应性突变的受试者的细胞和组织中积累的体细胞线粒体DNA控制区（CR）和重排突变的程度。最后，我们将对适应极端气候的小鼠的线粒体 DNA 进行测序。如果它们也含有适应性 mtDNA 突变，则使用雌性 ES 细胞系将​​变异 mtDNA 谱系引入小鼠种系中。这些小鼠将培育出后代，测试它们对热和冷的敏感性、线粒体的生物化学和生理学、运动生理学和寿命。