A Novel Mechanism for Mitochondrial Regulation of Mammalian Longevity

描述(由申请人提供)：无脊椎动物和最近在老鼠中的一些线粒体电子传输链(ETC)突变被证明延长了寿命，这是一个自相矛盾的结果。我的实验室正在研究其中一个模型，Surf1/-小鼠，它缺乏Surf1，一种ETC复杂的IV组装蛋白，结果是复杂的IV活性降低，中位寿命惊人地增加(20%-25%)。最近在Celegans上的一项研究还报告说，通过RNAi将复合体IV还原为cco1可以延长寿命，此外，即使当复合体IV的还原仅限于神经元或肠道时，也可以实现寿命的延长(Durieux等人，2011年)。这与之前的一项研究一致，该研究表明，减少针对果蝇神经元组织的Surf1会导致寿命延长(Zordan等人，2006年)。Cco1线虫突变体的延长寿命被证明需要线粒体未折叠蛋白反应(MtUPR)的诱导，这是一种线粒体应激反应途径。更重要的是，复合体IV中神经元特异性的减少被证明可以诱导远端组织(肠)中的mtUPR，并与延长寿命相关。综上所述，这些发现表明了一种新的途径，通过这种途径，一个组织中线粒体功能的变化可以通知远端组织的变化，并影响整个有机体的衰老。目前这项研究的目的是确定类似的机制是否发生在哺乳动物身上，即线粒体功能的组织特异性改变能否通过以下方式调节远端组织的衰老 一条信号通路？我们建议检验这样的假设，即组织特异性地减少复合体IV将产生远端组织感受到的系统释放的信号，线粒体应激反应途径(mtUPR和线粒体生物发生)的上调以及代谢的改变，这可能有助于延长寿命。我们已经产生了有条件的Surf1小鼠，它将允许我们在特定组织中删除Surf1，以确定组织特异性抑制复合体IV是否会增加远端组织中的线粒体应激反应途径。我们已经证明，长期存活的Surf1/-小鼠的组织中，包括大脑和脂肪组织在内的几个组织中mtUPR表达上调，同时代谢发生显著变化，胰岛素敏感性增加。在这里，我们将确定小鼠体内组织特异性(脑和脂肪组织)复合体IV的减少是否可以在其他组织中诱导线粒体应激反应途径，以及这些变化是否会引发我们在Surf1-/-小鼠中测量的相同有益的代谢变化。我们还将启动实验，利用质谱学和蛋白质组学技术，确定负责组织间信号传递的潜在信号因子(或有丝分裂因子)。一个组织中的线粒体通过分泌因子在远端组织中进行通讯和调节功能的潜力是一个令人兴奋的新概念，它可能代表着我们对线粒体功能在衰老中作用的理解的范式转变。

DESCRIPTION (provided by applicant): A number of mitochondrial electron transport chain (ETC) mutants in invertebrates and recently in mice have been shown to exhibit increased longevity, a paradoxical result. My laboratory is studying one of these models, Surf1-/- mice, that lack Surf1, an ETC Complex IV assembly protein and as a result have reduced complex IV activity and a surprising increase in median lifespan (20-25%). A recent study in C elegans also reported that reduced complex IV achieved by RNAi to cco1 increases lifespan, and furthermore that lifespan extension can be achieved even when complex IV reduction is restricted to neurons or intestine (Durieux et al., 2011). This is consistent with a previous study showing that reduction of Surf1 targeted to neuronal tissue in Drosophila leads to increased lifespan (Zordan et al., 2006). The extended lifespan in the cco1 C elegans mutants was shown to require the induction of the mitochondrial unfolded protein response (mtUPR), a mitochondrial stress response pathway. More importantly, neuron specific reduction in complex IV was shown to induce the mtUPR in a distal tissue (intestine) in association with increased lifespan. Taken together, these findings suggest a novel pathway by which alterations in mitochondrial function in one tissue can signal changes in a distal tissue and impact aging in the whole organism. The goal of the current study is to determine whether similar mechanisms occur in mammals, i.e., can a tissue-specific alteration in mitochondrial function regulate aging in distal tissues through a signaling pathway? We propose to test the hypothesis that tissue-specific reduction of complex IV will generate a systemically released signal sensed by distal tissues, up-regulation of mitochondrial stress response pathways (mtUPR and mitochondrial biogenesis) and alterations in metabolism that could contribute to increased lifespan. We have generated conditional Surf1 mice that will allow us to delete Surf1 in specific tissues to determine whether tissue-specific inhibition of complex IV confers an increase mitochondrial stress response pathways in distal tissues. We have shown that tissues from the long-lived Surf1-/- mice have up-regulation of the mtUPR in several tissues including brain and adipose tissue, along with significant alterations in metabolism and increased insulin sensitivity. Here we will determine whether a tissue-specific (brain and adipose tissue) reduction in complex IV in mice can induce mitochondrial stress response pathways in other tissues and whether these changes initiate the same beneficial metabolic changes we measured in Surf1-/- mice. We will also initiate experiments to define the potential signaling factor (or mitokine) responsible for signaling between tissues using mass spectrometry and proteomic techniques. The potential for mitochondria in one tissue to communicate and modulate function in distal tissues through a secreted factor is an exciting and novel concept that could represent a paradigm shift in our understanding of the role of mitochondrial function in aging.