Aging-related mitochondrial degeneration and degenerative diseases

描述(申请人提供)：线粒体功能随年龄增长而退化。我们建议的总体目标是(1)更好地了解衰老是如何导致线粒体退化的，以及(2)确定目前已知的抗氧化机制以外的细胞途径，这些机制可能会延缓线粒体的退化过程。在之前的资助期间，我们为成人/晚发型神经肌肉退行性疾病常染色体显性遗传性进行性外眼肌麻痹(Adpeo)建立了酵母模型，该疾病是由腺嘌呤核苷酸转位酶(Ant)的功能获得突变引起的。ANT通常参与跨越线粒体内膜的ADP/ATP交换。我们发现，酵母中的等量突变会导致衰老依赖的线粒体去极化和衰老抑制素突变。这些独特的实验系统使我们能够毫不含糊地证明，减少胞浆蛋白质合成可以有力地抑制衰老依赖的线粒体退化。这一发现揭示了细胞蛋白质稳态(或蛋白质稳态)和线粒体功能完整性之间的一种意想不到的联系。在最近对抗变性抑制基因的遗传筛选中，我们发现了与胞质mRNA衰退和蛋白质降解有关的基因。这些蛋白抑制基因/途径中有几个已知的人类同源基因在退行性疾病中发生了突变。这些观察结果导致了我们的中心假设，即胞浆中蛋白质稳态的丧失可能会导致线粒体内膜上的蛋白质稳态压力，从而影响能量稳态和衰老细胞的适合性。为了测试这一点，我们提出了以下目标：(1)我们将检查复制衰老过程中细胞蛋白平衡和线粒体完整性之间的联系。我们将专门确定导致蛋白质表型易于处理的退行性细胞死亡的mRNA缺陷和蛋白质降解是否存在。这些表型也独立地被捕获从细胞质的PRO超载，一般可加速衰老依赖的线粒体退变；(2)我们将测试胞浆中的蛋白质平衡应激可能影响蛋白质稳态，呼吸复合体的生物发生，生物能量效率和线粒体内膜的结构完整性的假说；(3)通过利用我们研究中发现的抗变性基因，我们将检查这些基因的过度表达是否可以改善线粒体膜的完整性和能量转导，从而延长细胞的寿命。由于细胞蛋白平衡下降是衰老和一些退行性疾病的常见分子症状，我们的研究可能有助于我们更好地了解这些条件下线粒体退变的机制。

DESCRIPTION (provided by applicant): Mitochondrial function degenerates with aging. The overall goals of our proposal are (1) to better understand how aging induces mitochondrial degeneration and (2) to identify cellular pathways other than the currently known anti-oxidative mechanisms that can potentially delay the degenerative process. In the previous grant period, we developed a yeast model for the adult/late-onset neuromuscular degenerative disease autosomal dominant Progressive External Ophthalmoplegia (adPEO), caused by gain-of-function mutations in the adenine nucleotide translocase (Ant). Ant is normally involved in ADP/ATP exchange across the mitochondrial inner membrane. We found that equivalent mutations in yeast induce aging-dependent mitochondrial depolarization and -aging prohibitin mutants. These unique experimental systems enabled us to unequivocally demonstrate that reducing cytosolic protein synthesis can robustly suppress aging-dependent mitochondrial degeneration. This finding reveals an unanticipated link between cellular protein homeostasis (or proteostasis) and the functional integrity of mitochondria. In a recent genetic screen for anti-degenerative suppressors, we identified genes involved in cytosolic mRNA decay and protein degradation. Several of these proteostatic genes/pathways have human orthologs known to be mutated in degenerative diseases. These observations led to our central hypothesis that loss of protein homeostasis in the cytosol may induce proteostatic stress on the mitochondrial inner membrane, which consequently affects energy homeostasis and the fitness of aged cells. To test this, we propose the following aims: (1) We will examine the link between cellular proteostasis and mitochondrial integrity during replicative aging. We will specifically determine whether defects in mRNA decay and protein degradation, which cause protein phenotypically tractable degenerative cell death. These phenotypes were also independently captured in the pro overloading from the cytosol, can generally accelerate aging-dependent mitochondrial degeneration; (2) We will test the hypothesis that cytosolic proteostatic stress may affect protein homeostasis, respiratory complex biogenesis, bioenergetic efficiency and structural integrity of the mitochondrial inner membrane; and (3) By taking advantage of the anti-degenerative genes identified in our study, we will examine whether over-expression of these genes, which improves mitochondrial membrane integrity and energy transduction, extends cell's lifespan. Because decline of cellular proteostasis is a common molecular symptom of aging and some degenerative diseases, our studies may help us better understand the mechanism of mitochondrial degeneration under these conditions.