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AAA ATPases linking mitochondria with microtubule processing in flies and yeast

果蝇和酵母中连接线粒体与微管加工的 AAA ATP 酶

基本信息

批准号：
8289834
负责人：
KAREN G HALES
金额：
$ 32.08万
依托单位：
DAVIDSON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289834
关键词：
ATP phosphohydrolase Affect Alleles Autosomal Dominant Optic Atrophy Biochemical Biological Models Cells Cellular biology Centrosome Charcot-Marie-Tooth Disease Collaborations Cytokinesis Data Defect Development Disease Dissection Drosophila genus Drosophila melanogaster Family Family member Fertility Food Energy Gene Family Genes Genetic Genome Goals Health Hereditary Spastic Paraplegia Homologous Gene Human Human Genetics Infertility Link Maps Mediating Mediator of activation protein Meiosis Merozoite Surface Protein 1 Microtubules Mitochondria Mitochondrial Proteins Molecular Morphogenesis Movement Mutation Myopathy Nervous system structure Neurodegenerative Disorders Neurons Neuropathy Organelles Orthologous Gene Parkinson Disease Participant Phenotype Premature aging syndrome Process Proteins RNA Interference Relative (related person)Research Role Saccharomyces cerevisiae Shapes Spastic Paraplegia Sperm Tail Spermatids Spermatogenesis Staging Sterility Structure Syndrome Testing Testis Tissues Universities Utah Work Yeasts base cell type fly genetic analysis insight katanin kinetosome knockout gene male mitochondrial dysfunction mutant paralogous gene receptor internalization spastin sperm cell therapy design

项目摘要

DESCRIPTION (provided by applicant): Mitochondria, the organelles in which food energy is harnessed into usable ATP form, are moved and shaped to fulfill different energy needs within specialized cells. Many human genetic neurodegenerative disorders are associated with defects of mitochondrial dynamics. Drosophila melanogaster spermatogenesis is an ideal model system for genetic dissection of conserved mechanisms of mitochondrial morphogenesis, since mitochondria undergo dramatic shaping during sperm development. After meiosis, all mitochondria in a Drosophila spermatid normally fuse into two giant mitochondrial derivatives that interwrap precisely and intricately to form a spherical structure called the Nebenkern, which then unfurls and elongates along the growing sperm tail. The main focus is to elucidate molecular mechanisms underlying mitochondrial shaping, as a way to characterize genes whose human homologs might underlie mitochondrial dysfunction. We previously identified the Drosophila nmd gene (no mitochondrial derivative) as required for aggregation of mitochondria during spermatogenesis. The Nmd gene product is an AAA ATPase related to microtubule-severing proteins spastin and katanin, though unlike those relatives, Nmd is unique in its localization to both mitochondria and centrosomes/basal bodies. A paralog of Nmd, CG4701, is required for mitochondrial shaping later in spermatogenesis. Both paralogs seem to be required also for male meiotic cytokinesis, perhaps through effects on the meiotic spindle. A yeast ortholog exists but has not been well characterized. Since various observations initially suggest a conserved role for Nmd family members in both mitochondrial shaping and microtubule processing, the primary emphasis in the proposed research is to determine genetically and biochemically the interactions between these mitochondrial AAA ATPases (in both flies and yeast) and microtubules and other structures. These gene products are homologous to human protein ATAD1 which is important in neurons for internalization of receptors but about which little else is known. ATAD1 may be a good candidate for another version of spastic paraplegia that maps in the same region of the genome. Our work will allow for important insight into the molecular roles of this human gene in health and disease. As a final aim, the genes defective in two male sterile Drosophila strains with related phenotypes to nmd and CG4701 will be identified, allowing identification of further gene families that may ultimately be associated with human mitochondrial neuropathies, myopathies, and infertility syndromes. PUBLIC HEALTH RELEVANCE: Defects of mitochondrial shaping and movement underlie many neurodegenerative diseases and may be associated with premature aging as well as infertility. Elucidation of molecular mechanisms by which mitochondrial shaping is mediated by fly and yeast mitochondrial proteins related to those implicated in hereditary spastic paraplegia will enable characterization of related functions in humans. These efforts may provide a deeper understanding of mitochondria-related disorders and set the stage for the design of treatments.

描述（由申请人提供）：线粒体是将食物能量转化为可用ATP形式的细胞器，在特定细胞内被移动和塑造以满足不同的能量需求。许多人类遗传性神经退行性疾病都与线粒体动力学缺陷有关。由于线粒体在精子发育过程中经历了戏剧性的塑造，因此黑腹果蝇的精子发生是线粒体形态发生保守机制遗传解剖的理想模型系统。在减数分裂后，果蝇精子中的所有线粒体通常融合成两个巨大的线粒体衍生物，它们精确而复杂地缠绕在一起，形成一个称为Nebenkern的球形结构，然后沿着生长中的精子尾部展开并拉长。主要重点是阐明线粒体形成的分子机制，作为一种表征人类同源基因可能导致线粒体功能障碍的方法。我们之前发现果蝇nmd基因（无线粒体衍生物）是精子发生过程中线粒体聚集所必需的。Nmd基因产物是一种与微管切断蛋白spastin和katanin相关的AAA atp酶，尽管与这些亲缘蛋白不同，Nmd在线粒体和中心体/基底体中都有独特的定位。Nmd的一种类似物CG4701在精子发生后期的线粒体形成中是必需的。男性减数分裂细胞质分裂似乎也需要这两种类比，可能是通过对减数分裂纺锤体的影响。存在一种酵母同源物，但尚未很好地表征。由于各种观察结果最初表明Nmd家族成员在线粒体形成和微管加工中都具有保守作用，因此拟议研究的主要重点是确定这些线粒体AAA atp酶（在果蝇和酵母中）与微管和其他结构之间的遗传和生化相互作用。这些基因产物与人类蛋白ATAD1同源，ATAD1在神经元中对受体的内化很重要，但对其知之甚少。ATAD1可能是另一种痉挛性截瘫的一个很好的候选基因，它位于基因组的同一区域。我们的工作将使我们能够深入了解这种人类基因在健康和疾病中的分子作用。最终目的是鉴定与nmd和CG4701表型相关的两个雄性不育果蝇菌株的缺陷基因，从而鉴定可能最终与nmd和CG4701相关的进一步基因家族