Modulating mitochondrial function to promote proteostasis in the aging lung

项目摘要 65岁或以上的人占每年甲型流感病毒死亡人数的80-90%。的 这个项目的首要目标是系统地测试调节线粒体功能的假设， 可以改变甲型流感感染后的肺修复。在第一个周期中，我们在C中生成数据。elegans模型 提示在衰老过程中线粒体电子传递能力的轻度降低促进了蛋白质稳定。 为了在哺乳动物系统中测试这一假设，我们开始使Ndufs 2杂合（Ndufs 2 +/-）小鼠老化。Ndufs2 是线粒体电子传递链复合物I的催化亚基。NDUFs 2杂合子小鼠具有 最大线粒体复合物I容量减少50%，但在一岁之前表现正常。在 相反，我们的初步数据表明，肺泡上皮细胞中Ndufs 2的完全缺失导致死亡， 老鼠在年轻的时候有趣的是，线粒体复合物I的辅助亚基Ndufs 4的缺失， 导致约80%的线粒体复合物I功能丧失（低形态），在基线时不引起肺病理学。 这使我们假设线粒体复合物I功能的轻度降低将改善恢复 在甲型流感感染后，虽然更严重的减少将诱导高水平的ATF 4，这将损害肺 修复.我们的初步数据还表明，调节性T细胞（Tcells，Tcells）是肺泡上皮细胞增殖所必需的。 甲型流感病毒感染后的修复。来自老年小鼠的TCRs具有增加的DNA超甲基化， 无法修复甲型流感病毒引起的肺损伤。因此，我们将确定是否部分或全部损失 线粒体复合物I功能的降低阻止了甲型流感病毒感染后的肺修复。集体 这些假设将在三个相互关联的特定目的中进行检验：（1）线粒体最大能量的下降是否 复合物I功能（Ndufs 2 +/-小鼠）在整个寿命期间改善了从甲型流感诱导的肺炎中的恢复。 衰老(2)ATF 4激活是否是由完全免疫抑制剂诱导的甲型流感诱导的肺损伤增加所必需的？ 肺泡上皮细胞线粒体复合物I功能的丧失或亚型？(3)是完全丧失还是 线粒体复合物I亚型在调节性T细胞（TCFs）中的功能足以抑制其 促进肺损伤后的组织修复

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?