A Novel Mechanism for Mitochondrial Regulation of Mammalian Longevity

描述（由申请人提供）：无脊椎动物和最近小鼠中的许多线粒体电子传递链（ETC）突变体显示出寿命延长，这是一个矛盾的结果。我的实验室正在研究这些模型之一，Surf 1-/-小鼠，缺乏Surf 1，ETC复合物IV组装蛋白，因此降低了复合物IV的活性，并令人惊讶地增加了中位寿命（20-25%）。最近在秀丽线虫中的研究也报道了通过RNAi至cco 1实现的复合物IV的减少增加了寿命，并且此外，即使当复合物IV减少限于神经元或肠时，也可以实现寿命延长（Durieux et al.，2011年）。这与先前的研究一致，该研究表明果蝇中靶向神经元组织的Surf 1的减少导致寿命增加（Zordan et al.，2006年）。cco 1线虫突变体的寿命延长需要诱导线粒体未折叠蛋白反应（mtUPR），这是一种线粒体应激反应途径。更重要的是，复合物IV中的神经元特异性减少显示出诱导远端组织（肠）中的mtUPR，其与寿命增加相关。总之，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改变可以发出远端组织变化的信号，并影响整个生物体的衰老。目前研究的目标是确定类似的机制是否发生在哺乳动物中，即，线粒体功能的组织特异性改变是否可以通过 信号通路吗我们建议测试的假设，组织特异性减少复合物IV将产生系统释放的信号，远端组织，线粒体应激反应途径（mtUPR和线粒体生物发生）的上调和代谢的改变，可能有助于增加寿命。我们已经产生了条件性Surf 1小鼠，这将使我们能够删除特定组织中的Surf 1，以确定复合物IV的组织特异性抑制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，来自长寿Surf 1-/-小鼠的组织在包括脑和脂肪组织在内的几种组织中具有mtUPR的上调，沿着代谢的显著改变和胰岛素敏感性的增加。在这里，我们将确定小鼠中复合物IV的组织特异性（脑和脂肪组织）减少是否可以诱导其他组织中的线粒体应激反应途径，以及这些变化是否会引发我们在Surf 1-/-小鼠中测量的相同的有益代谢变化。我们还将启动实验，以确定潜在的信号传导因子（或丝裂因子）负责使用质谱和蛋白质组学技术组织之间的信号。一个组织中的线粒体通过分泌因子在远端组织中交流和调节功能的潜力是一个令人兴奋的新概念，它可能代表我们对线粒体功能在衰老中的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.