CLU1: a regulator of mitochondrial distribution and translation of nuclear-encoded mitochondrial proteins

CLU1:线粒体分布和核编码线粒体蛋白翻译的调节因子

基本信息

项目摘要

Mitochondria are essential organelles, implicated in ATP production, crucial metabolic processes, calcium buffering, and cell death. Mitochondria distribution in cells is crucial for their function, especially in highly polarized cells as neurons, where mitochondria travel long distances to reach regions of high ATP demand in axons and dendrites. The vast majority of mitochondrial proteins are synthesized in the cytosol and imported in the organelle. This raises the important question whether synthesis of nuclear-encoded mitochondrial proteins occurs close to the organelle. We have identified mammalian CLU1 as a candidate molecule regulating both translation of nuclear encoded mitochondrial proteins and mitochondrial distribution. CLU1 is highly conserved during evolution, from Arabidopsis thaliana to humans. In plant, yeast, and Drosophila melanogaster, CLU1 knock-out leads to clustering of mitochondria close to the nucleus. We have evidence that mammalian CLU1 can similarly affect mitochondrial distribution in cells. Moreover, we find that CLU1 is a ribosomal-associated protein, which directly binds RNA. In addition, CLU1 interacts with the astrin-SKAP complex, which is implicated in kinetochore separation during mitosis. An attractive hypothesis is that CLU1 might regulate the translation of nuclear-encoded mitochondrial proteins, or the transport of a subset of ribonucleoparticles close to mitochondria, thereby affecting mitochondrial distribution. Here we propose to: 1) investigate a possible the role of CLU1 in regulation of translation of nuclear-encoded mitochondrial proteins, by identifying target mRNAs which are bound by CLU1 and performing polysome profiling to assess the efficiency of their translation under different conditions; 2) identify the role of CLU1 interaction with the astrin-SKAP complex; 3) assess the physiological consequences of CLU1 knock-out in vivo in different tissues of the mouse.
线粒体是重要的细胞器,参与ATP的产生、重要的代谢过程、钙缓冲和细胞死亡。线粒体在细胞中的分布对于它们的功能至关重要,特别是在高度极化的细胞中,如神经元,其中线粒体长途旅行以到达轴突和树突中的高ATP需求区域。绝大多数线粒体蛋白质在细胞质中合成并输入细胞器。这就提出了一个重要的问题,即核编码的线粒体蛋白的合成是否发生在细胞器附近。我们已经确定哺乳动物CLU 1作为一个候选分子调节核编码的线粒体蛋白的翻译和线粒体分布。CLU 1在从拟南芥到人类的进化过程中高度保守。在植物、酵母和黑腹果蝇中,CLU 1敲除导致线粒体聚集在细胞核附近。我们有证据表明,哺乳动物CLU 1可以类似地影响细胞中的线粒体分布。此外,我们发现CLU 1是一种核糖体相关蛋白,它直接与RNA结合。此外,CLU 1与astrin-SKAP复合物相互作用,这与有丝分裂期间的动粒分离有关。一个有吸引力的假设是,CLU 1可能调节核编码的线粒体蛋白的翻译,或接近线粒体的核糖核颗粒的子集的运输,从而影响线粒体分布。在此,我们建议:1)通过鉴定与CLU 1结合的靶mRNA并进行多核糖体分析以评估它们在不同条件下的翻译效率,研究CLU 1在调节核编码的线粒体蛋白的翻译中的可能作用; 2)鉴定CLU 1与astrin-SKAP复合物的相互作用的作用; 3)评估CLU 1敲除在小鼠不同组织中的体内生理后果。

项目成果

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Professorin Dr. Elena Irene Rugarli其他文献

Professorin Dr. Elena Irene Rugarli的其他文献

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{{ truncateString('Professorin Dr. Elena Irene Rugarli', 18)}}的其他基金

The ERLINs as endoplasmic reticulum membrane scaffolds and their role in hereditary spastic paraplegia
ERLIN作为内质网膜支架及其在遗传性痉挛性截瘫中的作用
  • 批准号:
    387639709
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
    Research Grants
The cell-autonomous role of Afg3l2 in mitochondrial dynamics and neurodegeneration
Afg3l2 在线粒体动力学和神经退行性变中的细胞自主作用
  • 批准号:
    179734447
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Research Grants
PROSPAX: an integrated multimodal progression chart in spastic ataxias
PROSPAX:痉挛性共济失调的综合多模式进展图
  • 批准号:
    441409627
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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