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小鼠中的线粒体电子传递链（ETC）突变被证明可以延长寿命，这是一个矛盾的结果。我的实验室正在研究其中一种模型，Surf1-/-小鼠，缺乏Surf1， ETC复合体IV组装蛋白，因此复合体IV活性降低，中位寿命惊人地增加（20-25%）。最近一项关于秀丽隐杆线虫的研究也报道，通过RNAi降低cco1的复合体IV可以延长寿命，而且即使复合体IV的降低仅限于神经元或肠道，也可以延长寿命（Durieux et al., 2011）。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会延长果蝇的寿命（Zordan et al., 2006）。研究表明，秀丽隐杆线虫cco1c突变体的寿命延长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，神经元特异性复合物IV的减少被证明可以诱导远端组织（肠）的mtUPR，并与寿命增加有关。综上所述，这些发现提示了一种新的途径，通过这种途径，一个组织中线粒体功能的改变可以指示远端组织的变化，并影响整个生物体的衰老。本研究的目的是确定哺乳动物中是否存在类似的机制，即线粒体功能的组织特异性改变是否可以调节远端组织的衰老

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.