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；(2)识别除目前已知的抗氧化机制之外的细胞途径，这些途径可能会延迟退化过程。在之前的资助期内，我们开发了成人/晚发性神经肌肉退行性疾病常染色体显性进行性外眼肌麻痹（adPEO）的酵母模型，该疾病由腺嘌呤核苷酸转位酶（Ant）的功能获得突变引起。蚂蚁通常参与线粒体内膜上的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衰老抑制蛋白突变。这些独特的实验系统使我们能够明确地证明，减少胞质蛋白合成可以强有力地抑制衰老依赖的线粒体变性。这一发现揭示了细胞蛋白质稳态（或蛋白质稳态）与线粒体功能完整性之间意想不到的联系。在最近的抗退行性抑制基因筛选中，我们发现了参与细胞质mRNA衰变和蛋白质降解的基因。这些蛋白抑制基因/途径中有几种已知在退行性疾病中发生突变的人类同源物。这些观察结果导致了我们的中心假设，即细胞质中蛋白质稳态的丧失可能导致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)我们将研究在复制衰老过程中细胞蛋白质停滞和线粒体完整性之间的联系。我们将具体确定mRNA衰变和蛋白质降解中的缺陷是否会导致蛋白质表型上可处理的退行性细胞死亡。这些表型也被独立捕获在细胞质的前超载中，通常可以加速衰老依赖的线粒体变性；(2)我们将验证细胞质内蛋白稳态应激可能影响蛋白质稳态、呼吸复杂生物发生、生物能量效率和线粒体内膜结构完整性的假设；(3)利用我们研究中发现的抗退行性基因，我们将研究这些基因的过表达是否能改善线粒体膜的完整性和能量转导，延长细胞的寿命。由于细胞蛋白酶抑制能力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行性变的机制。

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.