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眼外肌麻痹（adPEO），这是一种由核编码蛋白（如腺嘌呤核苷酸移位酶亚型1（Ant 1））突变引起的成人发病神经肌肉退行性疾病。Ant 1催化ADP/ATP交换穿过线粒体内膜。它是激烈的争论，蚂蚁也可能通过参与线粒体膜的透化在细胞器启动的细胞死亡中发挥关键作用。我们最近的研究表明，在adPEO患者中Ant 1的致病等位基因导致模型酵母系统中的线粒体透化和退行性细胞死亡。一项平行的研究也表明Ant具有不同于ADP/ATP交换的新的生理功能。我们推测Ant的新细胞功能与膜通道有关，并且该通道的失调可能在adPEO细胞的线粒体膜透化和功能退化中起关键作用。该提案的主要目的是了解adPEO的致病机制和一般的Ant诱导的细胞死亡。更具体地，我们将（1）确定Ant诱导的细胞死亡的机制、基于Ant的通道的性质、adPEO相关的多分散性线粒体DNA缺失的起源，以及这些因素（例如，老化），其影响细胞群体中细胞死亡性状的发生。(2)我们将绘制Ant分子中的死亡结构域，并分离调节突变Ant的膜透化能力的反式作用元件。(3)我们将通过对来自酵母和人类的Ant分子进行遗传解剖来测试双功能性假设，并确定致病性膜透化通道的起源。该提案的独特之处在于使用了无与伦比的酵母系统，该系统允许对细胞死亡机制进行简单的遗传跟踪。 确定adPEO的确切致病因素可能会导致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了解Ant在细胞死亡中的确切作用，这反过来可能对过度细胞破坏导致的其他形式的退行性疾病具有广泛的适用性。

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.