Aging-related mitochondrial degeneration and degenerative diseases

描述（由申请人提供）：线粒体功能随着年龄的增长而退化。我们建议的总体目标是（1）更好地了解衰老如何诱导线粒体变性，以及（2）确定除目前已知的抗氧化机制之外的细胞途径，这些机制可能会延迟变性过程。在上一个资助期，我们开发了成人/迟发性神经肌肉退行性疾病常染色体显性进行性眼外肌麻痹（adPEO）的酵母模型，由腺嘌呤核苷酸移位酶（Ant）的功能获得性突变引起。Ant通常参与线粒体内膜的ADP/ATP交换。我们发现，酵母中的等效突变诱导衰老依赖的线粒体去极化和抗衰老抑制素突变体。这些独特的实验系统使我们能够明确地证明，减少胞质蛋白质合成可以有力地抑制衰老依赖性线粒体变性。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意外联系。在最近的抗变性抑制基因筛选中，我们确定了参与胞质mRNA衰变和蛋白质降解的基因。这些蛋白质抑制基因/途径中的几个具有已知在退行性疾病中突变的人类直系同源物。这些观察结果导致我们的中心假设，即细胞质中蛋白质稳态的丧失可能会诱导线粒体内膜上的蛋白质稳态应激，从而影响能量稳态和衰老细胞的适应性。为了验证这一点，我们提出了以下目标：（1）我们将研究在复制老化过程中细胞蛋白质稳态和线粒体完整性之间的联系。我们将特别确定是否在mRNA衰变和蛋白质降解，导致蛋白质表型易处理的退行性细胞死亡的缺陷。这些表型也独立地被捕获在来自胞质溶胶的pro超载中，通常可以加速衰老依赖的线粒体变性;（2）我们将检验胞质蛋白质稳态应激可能影响蛋白质稳态、呼吸复合物生物合成、生物能量效率和线粒体内膜结构完整性的假设;（3）通过利用我们研究中发现的抗退化基因，我们将研究这些基因的过度表达是否会延长细胞的寿命，从而改善线粒体膜的完整性和能量转导。由于细胞蛋白质稳态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变性的机制。

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.