Modulating mitochondrial function to promote proteostasis in the aging lung

项目总结 65岁或65岁以上的人每年占甲型流感病毒死亡人数的80%-90%。这个 该项目的总体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部修复。在第一个周期中，我们在线虫模型中生成数据以 提示在衰老过程中线粒体电子传递能力的轻微下降促进了蛋白稳定。 为了在哺乳动物系统中验证这一假设，我们开始对Ndufs2杂合子(Ndufs2+/-)小鼠进行老化。Ndufs2 是线粒体电子传递链复合体I的催化亚单位。Ndufs2杂合子小鼠有 最大线粒体复合体I容量减少50%，但在一岁前看起来正常。在……里面 相反，我们的初步数据表明，肺泡上皮细胞中Ndufs2的完全缺失导致了死亡 在幼年时期的老鼠。有趣的是，线粒体复合体I的一个附属亚基Ndufs4的丢失，它 结果在~80%的线粒体复合体I功能丧失(低形态)的基础上，不会引起肺组织的病理改变。 这导致我们假设，线粒体复合体I功能的轻微减少将促进恢复 甲型流感感染后，虽然更严重的减少会导致高水平的ATF4，这将损害肺 修理。我们的初步数据还表明，调节性T细胞(Treg)对肺泡上皮细胞是必不可少的 甲型流感病毒感染后修复。来自老龄小鼠的Treg增加了DNA的超甲基化，并 无法修复甲型流感病毒引起的肺损伤。因此，我们将确定是部分损失还是全部损失 Tregs中线粒体复合体I功能的改变可以防止甲型流感病毒感染后的肺修复。集体地 这些假说将在三个相互关联的具体目标中得到检验：(1)最大线粒体是否下降 复合I功能(Ndufs2+/-小鼠)在整个生命周期内促进甲型流感肺炎的康复 衰老？(2)ATF4激活是否是A型流感所致肺损伤增加所必需的 肺泡上皮细胞线粒体复合体I功能丧失或形态减退？(3)是完全丧失还是 线粒体复合体I的低形态在调节性T细胞(Treg)中发挥作用，足以抑制它们的能力 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?