...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The PINK1/Parkin pathway regulates mitochondrial morphology
【24h】

The PINK1/Parkin pathway regulates mitochondrial morphology

机译：PINK1 / Parkin途径调节线粒体形态

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/ threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-of-function mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINKVParkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.
机译：PTEN诱导的激酶1（PINK1）或帕金基因中的功能丧失突变分别编码线粒体定位的丝氨酸/苏氨酸激酶和泛素蛋白连接酶，导致隐性家族性帕金森病。果蝇的遗传学研究表明，PINK1在一个影响帕金森上游的共同途径中起作用，该途径会影响包括飞行肌肉和多巴胺能神经元在内的一部分组织的线粒体完整性。尽管PINK1和parkin基因的突变导致线粒体肿大或肿胀，但PINK1和Parkin影响线粒体完整性的机制目前尚不清楚，这表明PINK1 / Parkin途径在线粒体形态中可能具有调节作用。为了解决这个假设，我们研究了影响PINK1和parkin突变体表型控制线粒体形态的机制的遗传改变的影响。我们报告说，编码关键的线粒体裂变促进成分的drp1的杂合功能丧失突变在PINK1或parkin突变体背景下具有极大的致死性。相反，由drp1基因剂量增加和影响线粒体融合促进因子OPA1和Mfn2的杂合功能丧失突变会强烈抑制由PINK1和parkin突变引起的飞行肌肉变性和线粒体形态改变。最后，我们发现与减少PINKVParkin途径活性相关的眼表型被减少线粒体裂变的扰动所抑制，并被减少线粒体融合的扰动所增强。我们的研究表明，PINK1 / Parkin途径促进线粒体裂变，而PINK1和parkin突变体中线粒体和组织完整性的丧失源自线粒体裂变的减少。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号