Modulating mitochondrial function to promote proteostasis in the aging lung

调节线粒体功能以促进衰老肺部的蛋白质稳态

• 批准号: 10620774
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 39.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620774
• 关键词: 1 year old; Acceleration; Age; Aging; Alveolar; Caenorhabditis elegans; Catalytic Domain; Cause of Death; Cell Death Induction; Cells; Cessation of life; Complex; Cytoprotection; DNA; Data; Disease; Electron Transport; Epithelial Cells; Epithelium; Exposure to; Functional disorder; Funding Opportunities; Goals; Heterozygote; Homeostasis; Human; Hypermethylation; Immune; Impairment; Individual; Infection; Influenza; Influenza A virus; Instruction; Knockout Mice; Longevity; Loss of Heterozygosity; Lung; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Mus; NADH; Natural regeneration; Oxidative Phosphorylation; Pathology; Pathway interactions; Phenotype; Pneumonia; Predisposition; Production; Proteins; Pulmonary Pathology; Reactive Oxygen Species; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Respiration; Respiratory physiology; Severities; Signal Transduction; Site; Stress; System; Testing; Tissues; Toxic effect; Virus Diseases; activating transcription factor; activating transcription factor 4; age related; aged; alveolar epithelium; biological adaptation to stress; cell age; human tissue; improved; lung injury; lung repair; normal aging; pharmacologic; prevent; proteostasis; repaired; response; small molecule; tissue repair

PROJECT SUMMARY Individuals aged 65 years or older account for 80-90% of deaths from influenza A virus each year. The overarching goal of this project is to systematically test the hypothesis that modulating mitochondrial function can alter lung repair after influenza A infection. In the first cycle, we generated data in the C. elegans model to suggest that the mild reduction in mitochondrial electron transport capacity during aging promotes proteostasis. To test this hypothesis in a mammalian system, we began to age Ndufs2 heterozygous (Ndufs2+/-) mice. Ndufs2 is a catalytic subunit of complex I of the mitochondrial electron transport chain. Ndufs2 heterozygous mice have a 50% reduction in maximal mitochondrial complex I capacity, but appear normal up to one year of age. In contrast, our preliminary data indicate that complete loss of Ndufs2 in alveolar epithelial cells causes the death of mice at a young age. Interestingly, loss of an accessory subunit of mitochondrial complex I, Ndufs4, which results in ~80% loss of mitochondrial complex I function (hypomorph), does not cause lung pathology at baseline. This has led us to hypothesize that mild reductions in mitochondrial complex I function will improve recovery after influenza A infection, while more severe reductions will induce high levels of ATF4 that will impair lung repair. Our preliminary data also indicate that regulatory T cells (Tregs) are essential for alveolar epithelial cell repair after influenza A virus infection. Tregs from aged mice have increased DNA hypermethylation and are unable to repair influenza A virus-induced lung injury. Thus, we will determine whether partial or complete loss of mitochondrial complex I function in Tregs prevents lung repair after influenza A virus infection. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Does a decline in maximal mitochondrial complex I function (Ndufs2+/- mice) over a lifespan improve recovery from influenza A-induced pneumonia during aging? (2) Is ATF4 activation required for the increase in influenza A-induced lung injury induced by the complete loss or hypomorph of mitochondrial complex I function in alveolar epithelial cells? (3) Is the complete loss or hypomorph of mitochondrial complex I function in regulatory T cells (Tregs) sufficient to dampen their ability to promote tissue repair after lung injury?

项目摘要 年龄在65岁或以上的人每年占流感病毒死亡的80-90％。这 该项目的总体目标是系统地测试调节线粒体功能的假设 流感A感染后可以改变肺修复。在第一个周期中，我们在秀丽隐杆线虫模型中生成了数据 表明在衰老期间，线粒体电子传输能力的轻度降低会促进蛋白质的抑制。 为了在哺乳动物系统中检验该假设，我们开始年龄NDUFS2杂合（NDUFS2 +/-）小鼠。 ndufs2 是线粒体电子传输链复合物I的催化亚基。 NDUFS2杂合小鼠具有 最大线粒体复合物I能力降低了50％，但最高年龄的正常。在 对比，我们的初步数据表明，肺泡上皮细胞中NDUFS2的完全损失导致死亡 年轻的老鼠。有趣的是，线粒体综合体I，NDUFS4的附件亚基损失 导致线粒体复合物I功能（Hypomorph）的损失约80％，在基线时不会导致肺病理。 这使我们假设线粒体复合物的轻度降低I功能将改善恢复 流感后感染后，虽然更严重的减少将诱导高水平的ATF4，这会损害肺 维修。我们的初步数据还表明，调节性T细胞（Tregs）对于肺泡上皮细胞至关重要 流感后的病毒感染后修复。老年小鼠的Treg具有增加的DNA高甲基化，为 无法修复流感病毒引起的肺损伤。因此，我们将确定部分还是完全损失 线粒体复合物I在Tregs中的功能可防止流感病毒感染后的肺修复。集体 这些假设将以三个相互关联的特定目的进行检验：（1）最大线粒体的下降 复杂的I功能（NDUFS2 +/-小鼠）在寿命中改善了流感A诱导的肺炎的恢复 老化？ （2）是ATF4激活需要完整的流感A诱导的肺损伤增加 线粒体复合物I在肺泡上皮细胞中功能的损失还是下对标？ （3）是完全损失或 线粒体复合物I在调节性T细胞（TREG）中的功能足以抑制其能力 肺部受伤后促进组织修复？