Impaired mitochondrial proteostasis in Alzheimer?s disease

线粒体参与关键的细胞过程，如能量供应和钙缓冲，这对细胞的生长至关重要。 神经元功能众所周知，线粒体在生理和生理条件下不断面临各种压力， 以及对维持线粒体稳态构成巨大挑战的病理状况。作为 作为细胞中的动态细胞器，线粒体不断地进行融合和分裂，以维持健康的细胞。 线粒体库此外，线粒体稳态还依赖于线粒体的质量控制系统， 蛋白质稳态线粒体伴侣蛋白和ATP依赖性蛋白酶形成复合物， 和功能上相互关联的系统来监测受损的蛋白质：线粒体伴侣蛋白参与 蛋白质移位和折叠反应，而ATP依赖性蛋白酶负责直接去除 错误折叠的蛋白质越来越多的证据表明，线粒体蛋白酶的缺陷 和伴侣蛋白引起线粒体功能障碍， 神经系统疾病在这方面，重要的是要注意，线粒体异常是一个早期的， 线粒体功能障碍是阿尔茨海默病（AD）的一个突出特征，越来越多的证据表明， 在AD的发病机制中起关键作用。然而，线粒体功能障碍的潜在机制， AD仍然难以捉摸。探讨线粒体质量控制系统的改变可能参与 AD的发病机制，我们进行了一项初步研究，以确定是否有任何变化的表达， 线粒体伴侣蛋白和蛋白酶在AD中的作用。事实上，我们发现， 线粒体基质蛋白酶（即，CLLP和LONP 1）。更重要的是， 对人脑活检样本的分析发现，线粒体电子致密内含物增加， 聚集的错误折叠的蛋白质，在线粒体中的易感神经元的AD皮层。这些数据 提示AD患者线粒体质量控制系统受损。我们的体外实验表明， 淀粉样蛋白β（Aβ）抑制线粒体蛋白酶复合物的活性。有趣的是， 线粒体蛋白酶可以拯救CRND 8小鼠原代神经元中的线粒体呼吸缺陷， AD的APP转基因小鼠模型。基于这些令人兴奋的初步数据，我们假设Aβ诱导 通过损害线粒体蛋白酶活性的异常线粒体蛋白质稳态和进一步的原因 线粒体功能障碍和神经元损失。为了检验这一假设，我们将描述因果作用， Aβ诱导的异常线粒体蛋白质稳态在体内和体外AD发病机制中的作用， 可能为疾病提供新的治疗靶点。

Mitochondria are involved in key cellular processes such as energy supply and calcium buffering critical for neuronal function. It is known that mitochondria are constantly facing various stresses under both physiological and pathological conditions which pose great challenge for the maintenance of mitochondrial homeostasis. As dynamic organelles in cells, mitochondria are continually undergoing fusion and fission to maintain a healthy mitochondrial pool. In addition, mitochondria homeostasis also relies on quality control system of mitochondrial proteostasis. It is well established that mitochondrial chaperones and ATP-dependent proteases form a complex and functionally interconnected system to monitor damaged proteins: mitochondrial chaperones are involved in protein translocation and folding reactions while ATP-dependent proteases are responsible for directly removing misfolded proteins from mitochondria. Increasing evidence demonstrated that defects in mitochondrial protease and chaperones cause mitochondrial dysfunction and have been associated with human diseases especially neurological disorders. In this regard, it is of importance to note that mitochondrial abnormality is an early prominent feature in Alzheimer’s disease (AD) and increasing evidence suggest that mitochondrial dysfunction plays a critical role in the pathogenesis of AD. However, mechanisms underlying mitochondrial dysfunction in AD remain elusive. To explore the potential involvement of an altered mitochondrial quality control system in the pathogenesis of AD, we undertook a pilot study to determine whether there is any change in the expression of mitochondrial chaperones and proteases in AD. Indeed, we found significantly decreased expression of mitochondrial matrix proteases (i.e., CLLP and LONP1) in AD brain tissues. More importantly, ultrastructure analysis of biopsy human brain samples uncovered increased mitochondrial electron dense inclusions, likely aggregations of misfolded proteins, in mitochondria in the susceptible neurons of AD cortex. These data suggested an impaired mitochondrial quality control system in AD. Our in vitro experiments demonstrated that amyloid-beta (Aβ) inhibits the activity of mitochondrial protease complexes. Interestingly, overexpression of mitochondrial proteases could rescue mitochondrial respiration deficits in primary neuron from CRND8 mice, an APP transgenic mouse model for AD. Based on these exciting preliminary data, we hypothesize that Aβ induces abnormal mitochondrial proteostasis by impairing the activity of mitochondrial proteases and further causes mitochondrial dysfunction and neuronal loss in AD. To test this hypothesis, we will characterize the causal role of Aβ-induced abnormal mitochondrial proteostasis in the pathogenesis of AD both in vivo and in vitro which will likely provide novel therapeutic targets of the disease.