Ant-induced cell death and human degenerative diseases

线粒体功能障碍促进衰老、细胞死亡，并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进行性外眼肌麻痹（adPEO），这是一种成人发病的神经肌肉退行性疾病，由核编码蛋白突变引起，如腺嘌呤核苷酸转位酶异构体1 （Ant1）。Ant1在线粒体内膜上催化ADP/ATP交换。蚂蚁也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中发挥关键作用，这是一个激烈的争论。我们最近的研究表明，adPEO患者的Ant1致病等位基因导致模型酵母系统的线粒体通透性和退行性细胞死亡。一项平行研究也表明，蚂蚁具有不同于ADP/ATP交换的新的生理功能。我们假设蚂蚁的新细胞功能与膜通道有关，并且该通道的失调可能在线粒体膜渗透和adPEO细胞的功能变性中起关键作用。该建议的主要目的是了解adPEO的致病机制和抗诱导的细胞死亡。更具体地说，我们将(1)确定蚂蚁诱导细胞死亡的机制，蚂蚁通道的性质，adpeo相关的多分散线粒体DMA缺失的起源，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)我们将绘制蚂蚁分子中的死亡结构域，并分离出调节突变蚂蚁膜渗透能力的反式作用元件。(3)我们将通过对酵母菌和人类蚂蚁分子的遗传解剖来验证双功能假说，并确定致病膜渗透通道的起源。该建议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的确切致病因素可以为该疾病的临床治疗制定适当的治疗策略。最重要的是，拟议研究的成功可能有助于更好地理解Ant在细胞死亡中的确切作用，而这反过来又可能广泛适用于由过度细胞破坏引起的其他形式的退行性疾病。

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.