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

基本信息

批准号：
7438806
负责人：
Xin Jie Chen
金额：
$ 12万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
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/7438806
关键词：
Adenine Nucleotide Translocase Adult Affect Age Aging Alleles Ants Cell Aging Cell Death Cell Survival Cell physiology Cells Chronic progressive external ophthalmoplegia Clinical Treatment Condition Death Domain Defect Degenerative Disorder Development Disease Dissection Elements Environmental Risk Factor Failure Genes Genetic Growth Human Inner mitochondrial membrane Investigation Ion Channel Laboratories Lead Maps Membrane Mitochondria Mitochondrial DNA Mitotic Modeling Mutagenesis Mutation Nature Nuclear Organelles Pathogenesis Patients Phenotype Physiological Play Ploidies Population Process Protein Isoforms Proteins Regulator Genes Research Personnel Role Screening procedure Secondary to System Testing Therapeutic Yeast Model System Yeasts base cell age disease-causing mutation gene complementation interest mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mutant novel programs respiratory success trait yeast genetics

项目摘要

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遗传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（如腺嘌呤核苷酸易位酶亚型 1 (Ant1)）突变引起。 Ant1 催化线粒体内膜上的 ADP/ATP 交换。 Ant 还可能通过参与线粒体膜的透化而在细胞器引发的细胞死亡中发挥关键作用，这一点备受争议。我们最近的研究表明，adPEO 患者中 Ant1 的致病等位基因会导致模型酵母系统中的线粒体透化和退行性细胞死亡。一项平行研究还表明，Ant 具有不同于 ADP/ATP 交换的新颖生理功能。我们假设 Ant 的新细胞功能与膜通道有关，并且通道的失调可能在线粒体膜透化和 adPEO 细胞功能退化中发挥关键作用。该提案的总体目标是了解 adPEO 的致病机制和 Ant 诱导的细胞死亡。更具体地说，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 相关的多分散线粒体 DMA 缺失的起源以及影响的因素（例如衰老）细胞群中细胞死亡特征的开始。 (2)我们将绘制Ant分子中的死亡结构域，并分离调节突变体Ant的膜通透能力的反式作用元件。 (3)我们将通过对酵母和人类的Ant分子进行基因解剖来检验双功能假说，并确定致病膜通透通道的起源。该提案的独特之处在于使用了无与伦比的酵母系统，可以轻松地对细胞死亡机制进行遗传追踪。确定 adPEO 的确切致病因素可能有助于制定适当的治疗策略来临床治疗该疾病。最重要的是，所提出的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，进而可以广泛适用于因细胞过度破坏而导致的其他形式的退行性疾病。