Ant-induced cell death and human degenerative diseases

蚂蚁诱导的细胞死亡和人类退行性疾病

• 批准号: 6871467
• 负责人: Xin Jie Chen
• 金额: $ 21.84万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871467
• 关键词: Saccharomyces; adenosine diphosphate; adenosine triphosphate; alleles; cell age; cell death; fungal genetics; gene expression; gene mutation; genetic mapping; human genetic material tag; membrane channels; membrane permeability; microorganism culture; mitochondrial DNA; mitochondrial disease /disorder; mitochondrial membrane; oxygen consumption; protein structure function; transport proteins

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.

线粒体功能障碍会促进细胞的衰老，细胞死亡以及最终的功能衰竭和变性。其中一个例子是常染色体显性进行性外科外科（ADPEO），这是一种由核编码蛋白突变引起的成年神经肌肉退行性疾病，例如腺嘌呤核苷酸易位酶同种型（ANT1）。 ANT1催化跨线粒体内膜的ADP/ATP交换。众所周知，蚂蚁也可能通过参与线粒体膜的通透性来在细胞器引发的细胞死亡中起关键作用。我们最近的研究表明，ADPEO患者ANT1的致病等位基因导致模型酵母系统中的线粒体通透性和退化性细胞死亡。一项平行研究还表明，ANT具有与ADP/ATP交换不同的新型生理功能。我们假设ANT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通透性和ADPEO细胞的功能变性中起关键作用。该提案的广泛目的是了解ADPEO的致病机制和抗Ant诱导的细胞死亡。更具体地说，我们将（1）确定抗Ant诱导的细胞死亡的机制，基于蚂蚁的通道的性质，与ADPEO相关的多分散分散性线粒体DMA缺失的起源以及影响细胞群体细胞死亡特征发作的因素（例如衰老）。 （2）我们将绘制蚂蚁分子和分离型跨作用元件中的死亡结构域，以调节突变蚂蚁的膜渗透能力。 （3）我们将通过酵母和人类的蚂蚁分子的遗传解剖来检验双方函数假设，并确定致病性膜 - 渗透通道的起源。该提案的独特性是使用无与伦比的酵母系统，该系统允许对细胞死亡机理的遗传跟踪。 确定ADPEO的确切致病因素可能会导致发展适当的治疗策略来对疾病进行临床治疗。最重要的是，拟议的研究的成功可能有助于更好地理解蚂蚁在细胞死亡中的确切作用，而细胞死亡可能对过度细胞破坏导致其他形式的退行性疾病具有广泛的适用性。