Ant-induced cell death and human degenerative diseases

线粒体功能障碍会促进衰老、细胞死亡，最终导致细胞功能衰竭和退化。其中一个例子是常染色体显性遗传性进行性外眼肌麻痹(Adpeo)，这是一种成人起病的神经肌肉退行性疾病，由核编码蛋白突变引起，例如腺嘌呤核苷酸转位酶异构体1(ANT1)。ANT1通过线粒体内膜催化ADP/ATP交换。Ant还可能通过参与线粒体膜的通透性，在细胞器启动的细胞死亡过程中发挥关键作用。我们最近的研究发现，在模型酵母系统中，adPEO患者ANT1的致病等位基因导致线粒体通透性和退行性细胞死亡。一项平行研究也表明，Ant具有不同于ADP/ATP交换的新的生理功能。我们推测Ant的新的细胞功能与膜通道有关，该通道的失调可能在adPEO细胞的线粒体膜通透性和功能退化中发挥关键作用。这项建议的广泛目标是了解adPEO的致病机制和蚂蚁诱导的细胞死亡。更具体地说，我们将(1)确定蚂蚁诱导细胞死亡的机制，基于蚂蚁的通道的性质，adPEO相关的多分散线粒体DMA缺失的来源，以及影响细胞群体中细胞死亡特征发生的因素(例如，衰老)。(2)我们将定位Ant分子中的死亡区域，并分离调节突变Ant膜通透性的反式作用元件。(3)我们将通过对酵母和人类Ant分子的遗传解剖来验证双功能假说，并确定致病性膜通透通道的起源。该方案的独特之处在于使用了无与伦比的酵母系统，可以轻松地对细胞死亡机制进行遗传跟踪。确定adPEO的确切致病因素可能导致制定适当的治疗策略用于该疾病的临床治疗。最重要的是，拟议研究的成功可能有助于更好地了解蚂蚁在细胞死亡中的确切作用，这反过来可能对其他形式的退行性疾病具有广泛的适用性，这些疾病是由过度的细胞破坏引起的。

Mitochondrial dysfunction promotes aging, cell death, and ultimately, functional failure and degeneration of the cell. One of the examples is autosomal dominant progressive external ophthalmoplegia (adPEO), an adult-onset neuromuscular degenerative disease caused by mutations in nuclear-encoded proteins, such as the adenine nucleotide translocase isoform 1 (Ant1). Ant1 catalyzes the ADP/ATP exchange across the mitochondrial inner membrane. It is intensively debated that Ant may also play a critical role in the organelle-initiated cell death by participating in the permeabilization of mitochondrial membranes. Our recent investigations have revealed that the pathogenic alleles of Ant1 in adPEO patients cause mitochondrial permeabilization and degenerative cell death in the model yeast system. A parallel study has also indicated that Ant has a novel physiological function distinct from ADP/ATP exchange. We hypothesize that the novel cellular function of Ant is related to a membrane channel, and that a dysregulation of the channel may play a critical role in mitochondrial membrane permeabilization and functional degeneration of adPEO cells. The broad objective of this proposal is to understand the pathogenic mechanism of adPEO and the Ant-induced cell death in general. More specifically, we will (1) determine the mechanism of the Ant-induced cell death, the nature of the Ant-based channel, the origin of the adPEO-associated polydisperse mitochondrial DMA deletions, and the factors (e.g., aging) that affect the onset of the cell death trait in cell populations. (2) We will map the death domains in the Ant molecule and isolate trans-acting elements that modulate the membrane-permeabilizing ability of the mutant Ant. (3) We will test the bifunctionality hypothesis by genetic dissection of Ant molecules from yeast and humans and determine the origin of the pathogenic membrane-permeabilizing channel. The uniqueness of the proposal is the use of the unparalleled yeast system that permits an easy genetic tracking of the cell death mechanism. Identifying the exact pathogenic factor of adPEO could lead to the development of adequate therapeutic strategies for clinical treatment of the disease. Most importantly, success of the proposed studies could contribute to a better understanding of the exact role of Ant in cell death, which in turn, could have a broad applicability to other forms of degenerative disease resulting from excessive cell destruction.